Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases

ABSTRACT

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.

This application claims priority to U.S. Provisional Application Ser.No. 61/119,844 filed Dec. 4, 2008, which is incorporated by reference inits entirety.

FIELD OF THE INVENTION

This invention pertains to compounds which inhibit the activity of Bcl-2anti-apoptotic proteins, compositions containing the compounds, andmethods of treating diseases during which anti-apoptotic Bcl-2 proteinsare expressed.

BACKGROUND OF THE INVENTION

Anti-apoptotic Bcl-2 proteins are associated with a number of diseases.There is therefore an existing need in the therapeutic arts forcompounds which inhibit the activity of anti-apoptotic Bcl-2 proteins.

Overexpression of Bcl-2 proteins correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem.

Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breastcancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies ofT-cell or D-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small cell lung cancer, prostate cancer,small cell lung cancer, spleen cancer, and the like is described incommonly-owned PCT US 2004/36770, published as WO 2005/049593, and PCTUS 2004/37911, published as WO 2005/024636.

Involvement of Bcl-2 proteins in immune and autoimmune diseases isdescribed in Current Allergy and Asthma Reports 2003, 3, 378-384;British Journal of Haematology 2000, 110 (3), 584-90; Blood 2000, 95(4), 1283-92; and New England Journal of Medicine 2004, 351 (14),1409-1419. Involvement of Bcl-2 proteins in arthritis is disclosed incommonly-owned U.S. Provisional Patent Application Ser. No. 60/988,479.Involvement of Bcl-2 proteins in bone marrow transplant rejection isdisclosed in commonly-owned U.S. patent application Ser. No. 11/941,196.

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,which are useful as inhibitors of anti-apoptotic Bcl-2 proteins, thecompounds having Formula I

wherein

-   A¹ is N or C(A²);

A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F,Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(1A);

E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, SO₂R¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷,C(O)NH₂, C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷, or NHSO₂R¹⁷; or

E¹ and Y¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², B¹, and D¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², D¹, and E¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂ N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂, or C(O)OR^(1A); or

A² and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

D¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂, or C(O)OR^(1A); or

A² and D¹, together with the atoms to which they are attached, arebenzene, naphthalene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

B¹, and E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is cycloalkyl, cycloalkenyl ar cycloalkynyl;

R² is phenyl, which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷,SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(10A);R^(10A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R¹²,OR¹², SR¹², S(O)R¹², SO₂R¹², C(O)R¹², CO(O)R¹², OC(O)R¹², OC(O)OR¹²,NH₂, NHR¹², N(R¹²)₂, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹², NR¹²S(O)₂R¹²,NHC(O)OR¹², NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹², NHC(O)N(R¹²)₂,NR¹²C(O)NHR¹², NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂,C(O)NHOH, C(O)NHOR¹², C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂, SO₂NHR¹²,SO₂N(R¹²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹², C(N)N(R¹²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(14A); R^(14A) is cycloalkane, cycloakene, heterocycloalkane orheterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(20A);R^(20A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R²²,OR²², SR²², S(O)R²², SO₂R²², C(O)R²², CO(O)R²², OC(O)R²², OC(O)OR²²,NH₂, NHR²², N(R²²)₂, NHC(O)R²², NR²²C(O)R²², NHS(O)₂R²², NR²²S(O)₂R²²,NHC(O)OR²², NR²²C(O)OR²², NHC(O)NH₂, NHC(O)NHR²², NHC(O)N(R²²)₂,NR²²C(O)NHR²², NR²²C(O)N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂,C(O)NHOH, C(O)NHOR²², C(O)NHSO₂R²², C(O)NR²²SO₂R²², SO₂NH₂, SO₂NHR²²,SO₂N(R²²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR²², C(N)N(R²²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloakane orheterocycloalkene;

R²⁴ is heteroarene, which is unfused or fused with benzene, heteroareneor R^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(25A);R^(25A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

Z¹ is R²⁶ or R²⁷;

Z² is R²⁸, R²⁹ or R³⁰;

Z^(1A) and Z^(2A) are both absent or are taken together to form CH₂,CH₂CH₂ or Z^(12A);

Z^(12A) is C₂-C₆-alkylene having one or two CH₂ moieties replaced by NH,N(CH₃), S, S(O) or SO₂;

L¹ is R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, C(O)R³⁷, CO(O)R³⁷, OC(O)R³⁷,OC(O)OR³⁷, NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO₂R³⁷, SO₂NH,SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R²⁶ is phenylene, which is unfused or fused with benzene or heteroareneor R^(26A); R^(26A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁷ is heteroarylene, which is unfused or fused with benzene orheteroarene or R^(27A); R^(27A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²⁸ is phenylene, which is unfused or fused with benzene, heteroarene orR^(28A); R^(28A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with benzene orheteroarene or R^(29A); R^(29A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkylene, cycloalkenylene, heterocycloalkylene orheterocycloalkenylene, each of which is unfused or fused with benzene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^(37A);

R^(37A) is alkylene, alkenylene, or alkynylene, each of which isunsubstituted or substituted with one or two or three independentlyselected R^(37B), OR^(37B), SR^(37B), S(O)R^(37B), SO₂R^(37B),C(O)R^(37B), CO(O)R^(37B), OC(O)R^(37B), OC(O)OR^(37B), NH₂, NHR^(37B),N(R^(37B))₂, NHC(O)R^(37B), NR^(37B)C(O)R^(37B), NHS(O)₂R^(37B),NR^(37B)S(O)₂R^(37B), NHC(O)OR^(37B), NR^(37B)C(O)OR^(37B), NHC(O)NH₂,NHC(O)NHR^(37B), NHC(O)N(R^(37B))₂, NR^(37B)C(O)NHR^(37B),NR^(37B)C(O)N(R^(37B))₂, C(O)NH₂, C(O)NHR^(37B), C(O)N(R^(37B))₂,C(O)NHOH, C(O)NHOR^(37B), C(O)NHSO₂R^(37B), C(O)NR^(37B)SO₂R^(37B),SO₂NH₂, SO₂NHR^(37B), SO₂N(R^(37B))₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR^(37B), C(N)N(R^(37B))₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃,CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl Br and I substituents;

R^(37B) is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(40A);R^(40A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the moieties represented by R²⁶ and R²⁷ are substituted (i.e.,if Z^(1A) and Z^(2A) are absent) or further substituted (i.e., if Z^(1A)and Z^(2A) are present) with one or two or three or four ofindependently selected R⁴¹, OR⁴¹, SR⁴¹, S(O)R⁴¹, SO₂R⁴¹, C(O)R⁴¹,CO(O)R⁴¹, OC(O)R⁴¹, OC(O)OR⁴¹, NH₂, NHR⁴¹, N(R⁴¹)₂, NHC(O)R⁴¹,NR⁴¹C(O)R⁴¹, NHS(O)₂R⁴¹, NR⁴¹S(O)₂R⁴¹, NHC(O)OR⁴¹, NR⁴¹C(O)OR⁴¹,NHC(O)NH₂, NHC(O)NHR⁴¹, NHC(O)N(R⁴¹)₂, NR⁴¹C(O)NHR⁴¹, NR⁴¹C(O)N(R⁴¹)₂,C(O)NH₂, C(O)NHR⁴¹, C(O)N(R⁴¹)₂, C(O)NHOH, C(O)NHOR⁴¹, C(O)NHSO₂R⁴¹,C(O)NR⁴¹SO₂R⁴¹, SO₂NH₂, SO₂NHR⁴¹, SO₂N(R⁴¹)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁴¹, C(N)N(R⁴¹)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl, which is unfused or fused with benzene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁴⁶,OR⁴⁶, SR⁴⁶, S(O)R⁴⁶, C(O)R⁴⁶, CO(O)R⁴⁶, OC(O)R⁴⁶, OC(O)OR⁴⁶, NH₂, NHR⁴⁶,N(R⁴⁶)₂, NHC(O)R⁴⁶, NR⁴⁶C(O)R⁴⁶, NHS(O)₂R⁴⁶, NR⁴⁶S(O)₂R⁴⁶, NHC(O)OR⁴⁶,NR⁴⁶C(O)OR⁴⁶, NHC(O)NH₂, NHC(O)NHR⁴⁶, NHC(O)N(R⁴⁶)₂, NR⁴⁶C(O)NHR⁴⁶,NR⁴⁶C(O)N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, C(O)NHOH, C(O)NHOR⁴⁶,C(O)NHSO₂R⁴⁶, C(O)NR⁴⁶SO₂R⁴⁶, SO₂NH₂, SO₂NHR⁴⁶, SO₂N(R⁴⁶)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁴⁶, C(N)N(R⁴⁶)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁴⁶ is alkyl, alkenyl, alkynyl, R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl, which is unfused or fused with benzene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(48A); R^(48A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(49A);R^(49A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the moieties represented by R⁴², R^(42A), R⁴³, R^(43A), R⁴⁴,R^(44A), R⁴⁷, R^(47A), R⁴⁸, R^(48A), R⁴⁹, and R^(49A) are independentlysubstituted with one or two or three or four of independently selectedR⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰, CO(O)R⁵⁰, OC(O)R⁵⁰,OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, NHC(O)R⁵⁰, NR⁵⁰C(O)R⁵⁰, NHS(O)₂R⁵⁰,NR⁵⁰S(O)₂R⁵⁰, NHC(O)OR⁵⁰, NR⁵⁰C(O)OR⁵⁰, NHC(O)NH₂, NHC(O)NHR⁵⁰,NHC(O)N(R⁵⁰)₂, NR⁵⁰C(O)NHR⁵⁰, NR⁵⁰C(O)N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰,C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁰SO₂R⁵⁰, SO₂NH₂,SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂,CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl,Br or I;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(51A); R^(51A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(52A); R^(52A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heteracycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(53A);R^(53A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁵⁵,OR⁵⁵, SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, C(O)R⁵⁵, CO(O)R⁵⁵, OC(O)R⁵⁵, OC(O)OR⁵⁵,NH₂, NHR⁵⁵, N(R⁵⁵)₂, NHC(O)R⁵⁵, NR⁵⁵C(O)R⁵⁵, NHS(O)₂R⁵⁵, NR⁵⁵S(O)₂R⁵⁵,NHC(O)OR⁵⁵, NR⁵⁵C(O)OR⁵⁵, NHC(O)NH₂, NHC(O)NHR⁵⁵, NHC(O)N(R⁵⁵)₂,NR⁵⁵C(O)NHR⁵⁵, NR⁵⁵C(O)N(R⁵⁵)₂, C(O)NH₂, C(O)NHR⁵⁵, C(O)N(R⁵⁵)₂,C(O)NHOH, C(O)NHOR⁵⁵, C(O)NHSO₂R⁵⁵, C(O)NR⁵⁵SO₂R⁵⁵, SO₂NH₂, SO₂NHR⁵⁵,SO₂N(R⁵⁵)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁵, C(N)N(R⁵⁵)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

wherein each foregoing cyclic moiety is independently unsubstituted,further unsubstituted, substituted or further substituted with one ortwo or three or four or five of independently selected R^(57A), R⁵⁷,OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, OC(O)R⁵⁷, OC(O)OR⁵⁷,NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷, NR⁵⁷C(O)R⁵⁷, NHS(O)₂R⁵⁷, NR⁵⁷S(O)₂R⁵⁷,NHC(O)OR⁵⁷, NR⁵⁷C(O)OR⁵⁷, NHC(O)NH₂, NHC(O)NHR⁵⁷, NHC(O)N(R⁵⁷)₂,NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷)₂, C(O)NH₂, C(O)NHR⁵⁷, C(O)N(R⁵⁷)₂,C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷, C(O)NR⁵⁷SO₂R⁵⁷, SO₂NH₂, SO₂NHR⁵⁷,SO₂N(R⁵⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁷, C(N)N(R⁵⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R^(57A) is spirocyclyl;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR⁵⁸; R⁵⁸A is cycloalkane, cycloalkane, heterocycloalkane orheterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R⁵⁹A; R^(59A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(60A);R^(60A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶²,OR⁶², SR⁶², S(O)R⁶², SO₂R⁶², C(O)R⁶², CO(O)R⁶², OC(O)R⁶², OC(O)OR⁶²,NH₂, NHR⁶², N(R⁶²)₂, NHC(O)R⁶², NR⁶²C(O)R⁶², NHS(O)₂R⁶², NR⁶²S(O)₂R⁶²,NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH₂, NHC(O)NHR⁶², NHC(O)N(R⁶²)₂,NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)₂,C(O)NHOH, C(O)NHOR⁶², C(O)NHSO₂R⁶², C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NHR⁶²,SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶², C(N)N(R⁶²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(63A); R^(63A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R⁶⁴A; R^(64A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(65A);R^(65A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁶ is alkyl, alkenyl or alkenyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶⁷,OR⁶⁷, SR⁶⁷, S(O)R⁶⁷, SO₂R⁶⁷, C(O)R⁶⁷, CO(O)R⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷,NH₂, NHR⁶⁷, N(R⁶⁷)₂, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷,NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂,C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NHR⁶⁷,SO₂N(R⁶⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R^(57A), R⁵⁸, R⁵⁹, R⁶⁰, R⁶³, R⁶⁴,R⁶⁵, and R⁶⁷ are unsubstituted or substituted with one or two or threeor four of independently selected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸, SO₂R⁶⁸,C(O)R⁶⁸, CO(O)R⁶⁸, OC(O)R⁶⁸, OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂, NHC(O)R⁶⁸,NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸, NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸, NR⁶⁸C(O)OR⁶⁸,NHC(O)NH₂, NHC(O)NHR⁶⁸, NHC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸, NR⁶⁸C(O)N(R⁶⁸)₂,C(O)NH₂, C(O)NHR⁶⁸, C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸, C(O)NHSO₂R⁶⁸,C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂, SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl which is unfused or fused with benzene, heteroarene orR^(69A); R^(69A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(70A); R^(70A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(71A);R^(71A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷² is alkyl, alkenyl or alkenyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁷³,OR⁷³, SR⁷³, S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, CO(O)R⁷³, OC(O)R⁷³, OC(O)OR⁷³,NH₂, NHR⁷³, N(R⁷³)₂, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³,NHC(O)OR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂,NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂,C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³,SO₂N(R⁷³)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

the moieties represented by R⁶⁹, R⁷⁰ , and R⁷¹ are unsubstituted orsubstituted with one or two or three or four of independently selectedNH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, OH,(O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I.

Another embodiment pertains to a compound having Formula (II)

or a therapeutically acceptable salt thereof, wherein

R¹⁰⁰ is as described for substituents on R²⁶;

n is 0, 1, 2, or 3;

R¹⁰¹ is as described for substituents on R⁴²;

m is 1, 2, 3, 4, or 5;

A¹ is N or C(A²);

A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F,Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(1A);

E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, SO₂R¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷,C(O)NH₂, C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷, or NHSO₂R¹⁷; or

E¹ and Y¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², B¹, and D¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, CO(O)R¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂), NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹,C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I,CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂, orC(O)OR^(1A); or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane, or heterocycloalkene; and

A², D¹, and E¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, CO(O)R¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂), NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹,C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I,CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ orC(O)OR^(1A); or

A² and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

D¹, E¹, and Y¹are independently selected H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹,C(O)R¹, CO(O)R¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹,NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂,NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹,NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂), NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH,C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹,NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H,CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

A² and D¹, together with the atoms to which they are attached, arebenzene, naphthalene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

B¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, CO(O)R¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂), NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R⁴A; R⁴Ais cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)CNH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷,SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C)is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(10A);R^(10A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R¹²,OR¹², SR¹², S(O)R¹², SO₂R¹², C(O)R¹², CO(O)R¹², OC(O)R¹², OC(O)OR¹²,NH₂, NHR¹², N(R¹²)₂, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹², NR¹²S(O)₂R¹²,NHC(O)OR₂, NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹², NHC(O)N(R¹²)₂,NR¹²C(O)NHR¹², NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂,C(O)NHOH, C(O)NHOR¹², C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂, SO₂NHR¹²,SO₂N(R¹²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹², CN(N)N(R¹²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br, I;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(14A); R^(14A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(20A);R^(20A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²¹ is alkyl, aikenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R²²,OR²², SR²², S(O)R²², SO₂R²², C(O)R²², CO(O)R²², OC(O)R²², OC(O)OR²²,NH₂, NHR²², N(R²²)₂, NHC(O)R²², NR²²C(O)R²², NHS(O)₂R²², NR²²S(O)₂R²²,NHC(O)OR²², NR²²C(O)OR²², NHC(O)NH₂, NHC(O)NHR²², NHC(O)N(R²²⁾ ₂,NR²²C(O)NHR²², NR²²C(O)N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂,C(O)NHOH, C(O)NHOR²², C(O)NHSO₂R²², C(O)NR²²SO₂R²², SO₂NH₂, SO₂NHR²²,SO₂N(R²²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR²², C(N)N(R²²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R²² is R²³, R²⁴ or R²⁵;

R²² is phenyl, which is unfused or fused with benzene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene, which is unfused or fused with benzene, heteroareneor R^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(25A);R^(25A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

Z² is R²⁸, R²⁹ or R³⁰;

Z^(1A) and Z^(2A) are both absent or are taken together to form CH₂,CH₂CH₂ or Z^(12A);

Z^(12A) is C₂-C₆-alkylene having one or two CH₂ moieties replaced by NH,N(CH₃), S, S(O) or SO₂;

L¹ is a R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, C(O)R³⁷, CO(O)R³⁷, OC(O)R³⁷,OC(O)OR³⁷, NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO₂R³⁷, SO₂NH,SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R²⁸ is phenylene, which is unfused or fused with benzene, heteroarene orR^(28A); R^(28A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with benzene orheteroarene or R^(29A); R^(29A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkylene, cycloalkenylene, heterocycloalkylene orheterocycloalkenylene, each of which is unfused or fused with benzene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^(37A);

R^(37A) is alkylene, alkenylene, or alkynylene, each of which isunsubstituted or substituted with one or two or three independentlyselected R^(37B), OR^(37B), SR^(37B), S(O)R^(37B), SO₂R^(37B),C(O)R^(37B), CO(O)R^(37B), OC(O)R^(37B), OC(O)OR^(37B), NH₂, NHR^(37B),N(R^(37B))₂, NHC(O)R^(37B), NR^(37B)C(O)R^(37B), NHS(O)₂R^(37B),NR^(37B)S(O)₂R^(37B), NHC(O)OR^(37B), NR^(37B)C(O)OR^(37B), NHC(O)NH₂,NHC(O)NHR^(37B), NHC(O)N(R^(37B))₂, NR^(37B)C(O)NHR^(37B),NR^(37B)C(O)N(R^(37B))₂, C(O)NH₂, C(O)NHR^(37B), C(O)N(R^(37B))₂,C(O)NHOH, C(O)NHOR^(37B), C(O)NHSO₂R^(37B), C(O)NR^(37B)SO₂R^(37B),SO₂NH₂, SO₂NHR^(37B), SO₂N(R^(37B))₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR^(37B), C(N)N(R^(37B))₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃,CF₂CF₃OCF₃, OCF₂CF₃F, Cl, Br and I substituents;

R^(37B) is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(40A);R^(40A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the moieties represented by R⁴² are independently substitutedwith one or two or three or four of independently selected R⁵⁰, OR⁵⁰,SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰, CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂,NHR⁵⁰, N(R⁵⁰)₂, NHC(O)R⁵⁰, NR⁵⁰C(O)R⁵⁰, NHS(O)₂R⁵⁰, NR⁵⁰S(O)₂R⁵⁰,NHC(O)OR⁵⁰, NR⁵⁰C(O)OR⁵⁰, NHC(O)NH₂, NHC(O)NHR⁵⁰, NHC(O)N(R⁵⁰)₂,NR⁵⁰C(O)NHR⁵⁰, NR⁵⁰C(O)N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂,C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁰SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰,SO₂N(R⁵⁰)₂, C(O)H, C(O)OH, C(N)NH₂, CCN)NHR⁵⁰, C(N)N(R⁵⁰)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(51A); R^(51A) is cycloalkane, cycloalkene, heterocycloalkene orheterocycloalkene;

R⁵² is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(52A); R^(52A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(53A);R^(53A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁵⁵,OR⁵⁵, SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, C(O)R⁵⁵, CO(O)R⁵⁵, OC(O)R⁵⁵, OC(O)OR⁵⁵,NH₂, NHR⁵⁵, N(R⁵⁵)₂, NHC(O)R⁵⁵, NR⁵⁵C(O)R⁵⁵, NHS(O)₂R⁵⁵, NR⁵⁵S(O)₂R⁵⁵,NHC(O)OR⁵⁵, NR⁵⁵C(O)OR⁵⁵, NHC(O)NH₂, NHC(O)NHR⁵⁵, NHC(O)N(R⁵⁵)₂,NR⁵⁵C(O)NHR⁵⁵, NR⁵⁵C(O)N(R⁵⁵)₂, C(O)NH₂, C(O)NHR⁵⁵, C(O)N(R^(5S))₂,C(O)NHOH, C(O)NHOR⁵⁵, C(O)NHSO₂R⁵⁵, C(O)NR⁵⁵SO₂R⁵⁵, SO₂NH₂, SO₂NHR⁵⁵,SO₂N(R⁵⁵)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁵, C(N)N(R⁵⁵)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

wherein each foregoing cyclic moiety is independently unsubstituted,further unsubstituted, substituted or further substituted with one ortwo or three or four or five of independently selected R^(57A), R⁵⁷,OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, OC(O)R⁵⁷, OC(O)OR⁵⁷,NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷, NR⁵⁷C(O)R⁵⁷, NHSO₂R⁵⁷, NR⁵⁷S(O)₂R⁵⁷,NHC(O)OR⁵⁷, NR⁵⁷C(O)OR⁵⁷, NHC(O)NH₂, NHC(O)NHR⁵⁷, NHC(O)N(R⁵⁷)₂,NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷⁾ ₂, C(O)NH₂, C(O)NHR⁵⁷, C(O)N(R⁵⁷)₂,C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷, C(O)NR⁵⁷SO₂R⁵⁷, SO₂NH₂, SO₂NHR⁵⁷,SO₂N(R⁵⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁷, C(N)NH(R⁵⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R^(57A) is spirocyclyl;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(58A); R^(58A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(59A); R^(59A) is cycloalkane, cycloalkene, heterecycloalkane orheterocycloalkene;

R⁶⁰is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(60A);R^(60A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶²,OR⁶², SR⁶², S(O)R⁶², SO₂R⁶², C(O)R⁶², CO(O)R⁶², C(O)R⁶², OC(O)OR⁶², NH₂,NHR⁶², N(R⁶²)₂, NHC(O)R⁶², NR⁶²C(O)R⁶², NHSO₂R⁶², NR⁶²S(O)₂R⁶²,NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH₂, NHC(O)NHR⁶², NHC(O)N(R⁶²⁾ ₂,NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)₂,C(O)NHOH, C(O)NHOR⁶², C(O)NHSO₂R⁶², C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NHR⁶²,SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶²), C(N)N(R⁶²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₃, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, Cl, Br or I;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(63A); R^(63A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(64A); R^(64A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(65A);R^(65A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁶ is alkyl, alkenyl or alkenyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶⁷,OR⁶⁷, SR⁶⁷, S(O)R⁶⁷, SO₂R⁶⁷, C(O)R⁶⁷, CO(O)R⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷,NH₂, NHR⁶⁷, N(R⁶⁷)₂, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷,NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂,C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NHR⁶⁷,SO₂N(R⁶⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R^(57A), R⁵⁸, R⁵⁹, R⁶⁰, R⁶³, R⁶⁴,R⁶⁵, and R⁶⁷ are unsubstituted or substituted with one or two or threeor four of independently selected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸, SO₂R⁶⁸,C(O)R⁶⁸, CO(O)R⁶⁸, OC(O)R⁶⁸, OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂, NHC(O)R⁶⁸,NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸, NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸, NR⁶⁸C(O)OR⁶⁸,NHC(O)NH₂, NHC(O)NHR⁶⁸, NHC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸, NR⁶⁸C(O)N(R⁶⁸)₂,C(O)NH₂, C(O)NHR⁶⁸, C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸, C(O)NHSO₂R⁶⁸,C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂, SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(69A); R^(69A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(70A); R^(70A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(71A);R^(71A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷² is alkenyl or alkenyl, each of which is unsnbstituted or substitutedwith one or two or three of independently selected R⁷³, OR⁷³, SR⁷³,S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, CO(O)R⁷³, OC(O)R⁷³, OC(O)OR⁷³, NH₂, NHR⁷³,N(R⁷³)₂, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³, NHC(O)OR⁷³,NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂, NR⁷³C(O)NHR⁷³,NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂, C(O)NHOH, C(O)NHOR⁷³,C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³, SO₂N(R⁷³)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

the moieties represented by R⁶⁹, R⁷⁰, and R⁷¹ are unsbustituted orsubstituted with one or two or three or four of independently selectedNH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, OH,(O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃s F, Cl, Br or I.

Still another embodiment pertains to a compound of Formula I or FormulaII, wherein A¹ is C(A²); and A² is H.

Still another embodiment pertains to a compound of Formula I or FormulaII, wherein A² is C(A²); A² is H; and B¹ is NHR¹.

Still another embodiment pertains to a compound of Formula I or FormulaII, wherein A¹ is C(A²); A² is H; B¹ is NHR¹; and D¹ is H.

Still another embodiment pertains to a compound of Formula I or FormulaII, wherein A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; and E¹ is H.

Still another embodiment pertains to a compound of Formula I or FormulaII, wherein A¹ is C(A²); A² is H; and B¹ is NHR¹; D¹ is H; E¹ is H; andY¹ is NO₂.

Still another embodiment pertains to compounds having Formula I, whichare

-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylamino)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((1-(methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((2methyl-1H-indol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxymethyl)phenoxy-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((1-methyl-1H-indol-4-)yl)oxy)benzamide;-   2-(3-(acetylamino)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(4-aminophenoxy-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(3-aminophenoxy-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyphenyl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-dimethylamino)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-cyanophenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1,3-benzothiazol-6-yl)oxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl))-2-((2-methyl-1,3-benzothiazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-((2-methyl-1,3-benzothiazol-5-yl)oxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimethylamino)-3-oxopropyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimethylamino)-2-oxoethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-dimethylamino)propyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)-N,N-dimethylbenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-morpholin-4-ylphenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dimethyl-1,3-thiazol-5-yl)phenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(3,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)ethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-isopropylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indazol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-ethylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1,2,2,6,6-pentamethylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((7-fluoro-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-((4′-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indazol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(3-(trifluoromethyl)phenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2-chloro-3-(trifluoromethyl)phenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopropylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1H-indol-4-yl)oxy)    -N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-morpholin-4-ylphenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((3-(3-morpholin-4-yl-3-oxopropyl)-1H-indol-5-yl)oxy)benzamide;-   2-(3-benzylxoy)phenoxy)-4-(4-((4′-chloro)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pryan-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-cyanophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpholin-4-yl-3-oxopropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpholin-4-ylpropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-(1H-imidazol-1-yl)-phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophenoxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   tert-butyl    4-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)benzyl(ethyl)carbamate;-   tert-butyl    3-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)benzyl(ethyl)carbamate;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-((ethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((ethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(4-(acetylamino)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   tert-butyl    4-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenylcarbamate;-   2-(1,1′-biphenyl-2-yloxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   tert-butyl    3-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenylcarbamate;-   2-(1,1′-biphenyl-3-yloxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(4-(benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-morpholin-4-ylphenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-1,3-benzothiazol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   tert-butyl    4-(3-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenyl)piperazine-1-carboxylate;-   2-(3-(benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-(benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morpholin-4-ylethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)benzamide;-   2-(4-benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   tert-butyl    4-(4-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)amino)carbonyl)phenoxy)phenyl)piperazine-1-caraboxylate;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-pyridin-4-ylphenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-4-ylphenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-3-ylphenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1H-benzimidazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-benzamide;-   4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylcarbamoyl)phenoxy)-N-(4-(3-morpholinopropylamino-3-nitrophenylsulfonyl)benzamide;-   4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propylamino)-3-nitrophenylsulfonyl)-2-(3-(methylcarbamoyl)phenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(dimethylamino)propyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-(hydroxymethyl)phenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-methoxybenzyl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrophenylsulfonyl-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide;-   4-(4-((4′-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide;-   N-{[4-{4-[(4′chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]-3-nitrobenzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(4-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-4-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2,3-difluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(3-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2,3-difluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(3-nitro-4-{[1-(thien-3-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(4-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-(2-fluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(1methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-({4-[(1-allylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)benzamide;-   2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide;-   2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(4-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[3-(methoxymethoxy)-2-methylphenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-hydroxy-2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-bromophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(3-iodophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2-phenylethyl)-piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3,4-dichlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-3,5-difluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-([3-hydroxymethyl)phenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(2-methoxyethoxy)ethyl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(2-chloro-3-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(3-phenylpropyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-ethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-hydroxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[6-(4-chlorophenyl)-1,3-benzodioxol-5-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(dimethylamino)-2-oxoethyl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-morpholin-4-ylethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[3-(1H-pyrrol-2-yl)phenoxy]benzamide;-   4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   tert-butyl    4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)amino]carbonyl}phenoxy)-1H-indole-1-carboxylate;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   Trans-2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(2-chlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   2-({1,3-bis[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-({3-[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)benzamide;-   2-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonylcarbamoyl)pheonxy)-N,N-dimethylbenzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-{[2-(trifluoromethyl)-1H-indol-4-yl]oxy}benzamide;-   2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   (4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-{[6-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-{[6-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide;-   2-[(2-amino-1,3-thiazol-4-yl)methoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   tert-butyl    4-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)amino]carbonyl}phenoxy)methyl]-1,3-thiazol-2-ylcarbamate;-   2-[(2-amino-1,3-thiazol-4-yl)methoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[3-(acetylamino)phenoxy]-(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[3-(acetylamino)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   2-[(2-chlorophenyl)amino]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-methoxy-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(2-chlorophenyl)amino]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   tert-butyl    5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]amino}carbonyl)phenoxy]-1H-indole-1-carboxylate;-   2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-[(6,7-difluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino-3-nitrophenyl]sulfonyl}benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-(4-amino-3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(3S,4R)-3-hydroxy-1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   2-(6-aminopyridin-3-yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   tert-butyl    5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate;-   2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyloxy)phenyl]sulfonyl}benzamide;-   2-[(3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   tert-butyl    5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;-   tert-butyl    4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;-   2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-[(5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   tert-butyl    5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-3-ylcarbamate;-   2-[5-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   tert-butyl    4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;-   2-[3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pryan-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-hydroxypyridin-3-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2-H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-{[6-(benzyloxy)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pryan-4ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro    2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[-(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   2-[(6-amino-5-fluoropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   N-{[5-bromo-6-(1,4-dioxan-2ylmethoxy)pyridino-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-N-({5-bromo-6-[(4-morpholin-4ylcyclohexyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   2-(3-amino-5-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3-nitrophenyl}sulfonyl)benzamide;-   N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[1-(4-methoxybenzyl)-1H-1,2,3-benzotriazol-4-yl]oxy}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}benzamide;-   Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)nicotinamide;-   2-amino-[(6-amino-5-cyanopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   2-{[6-(acetylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-methylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-isopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-cyclopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}benzamide;-   tert-butyl    6bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenyoxy)pyridin-2-ylcarbamate;-   tert-butyl    -4-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)pyridine-2,6-diyldicarbamate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[6-(cyclopropylamino)pyridin-3-yl]oxy}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-[(4-{[(4-(methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-{[5-chloro-6-(methylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-fluoro-1-(fluoromethyl)ethyl]morpholin-2yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(2-amino-6-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(2,6-diaminopyridin-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-3yl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   tert-butyl    5-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-({6-[(2,2,2-trifluoro)amino]pyridin-3-yl}oxy)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6fluoro-1H-indol-5-yl)oxy]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({9-(4-chlorophenyl)-3-[2-fluoro-1-(fluoromethyl)ethyl]-3-azaspiro[5.5]undec-8-en-8-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-[(2-amino-5-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[2-(1H-pyrazol-4-yl)phenoxy]benzamide;-   2-[2-(2-aminopyridin-3-yl)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-    ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[2-(1H-pyrazol-5-yl)phenoxy]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorphenyl-6,6-dimehyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

Still another embodiment pertains to2-[(6-amino-5-chloropyriidn-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-ntiro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;and therapeutically acceptable salts, prodrugs, salts of prodrug andmetabolites thereof.

Another embodiment pertains to a composition for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositioncomprising an excipient and a therapeutically effective amount of thecompound of Formula (I).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient a therapeutically effective amount ofFormula (I).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient therapeutically effective amount of thecompound of Formula (I) and a therapeutically effective amount of oneadditional therapeutic agent or more than one additional therapueticagent.

DETAILED DESCRIPTION OF THE INVENTION

Variable moieties herein are represented by identifiers (capital letterswith numerical and/or alphabetical superscripts) and may be specificallyembodied.

It is meant to be understood that proper valences are maintained for allmoieties and combinations thereof, that monovalent moieties having morethan one atom are drawn from left to right and are attached throughtheir left ends, and that divalent moieties are also drawn from left toright.

It is also meant to be understood that a specific embodiment of avariable moiety herein may be the same or different as another specificembodiment having the same identifier.

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond. The term “C_(x)-C_(y) alkyl” meansa straight or branched hydrocarbon chain containing at least onecarbon-carbon double bond containing x to y carbon atoms. The term“C₂-C₄ alkenyl” means an alkenyl group containing 2-4carbon atoms.Representative examples of alkenyl include, but are not limited tobuta-2,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” means a divalent group derived from a straight orbranched chain hydrocarbon of 2 to 4 carbon atoms and contains at leastone carbon-carbon double bond. The term “C_(x)-C_(y) alkylene” means a adivalent group derived from a straight or branched hydrocarbon chaincontaining at least one carbon-carbon double bond and containing x to ycarbon atoms. Representative examples of alkenylene include, but are notlimited to, —CH═CH— and —CH₂CH═CH—.

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term“C_(x)-C_(y) alkyl” means a straight or branched chain, saturatedhydrocarbon containing x to y carbon atoms. For example “C₂-C₁₀ alkyl”means a straight or branched chain, saturated hydrocarbon containing 2to 10 carbon atoms. Examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylene” means a divalent group derived from a straight orbranched, saturated hydrocarbon chain of 1 to 10 carbon atoms, forexample, of 1 to 4 carbon atoms. The term “C_(x)-C_(y) alkylene” means adivalent group derived from a straight or branched chain, saturatedhydrocarbon containing x to y carbon atoms. For example “C₂-C₆ alkylene”means a straight or branched chain, saturated hydrocarbon containing 2to 6 carbon atoms. Examples of alkylene include, but are not limited to,—CH₂, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and CH₂CH₂(CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. The term “C_(x)-C_(y) alkynyl”means a straight or branched chain hydrocarbon group containing from xto y carbon atoms. Representative examples of alkynyl include, but arenot limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,2-pentynyl, and 1-butynyl.

The term “alkynylene,” as used herein, means a divalent radical derivedfrom a straight or branched chain hydrocarbon group containing from 2 to10 carbon atoms and containing at least one carbon-carbon triple bond.

The term “aryl” as used herein, means phenyl.

The term “cyclic moiety,” as used herein, means benzene, phenyl,phenylene, cycloalkane, cycloalkyl, cycloalkylene, cycloalkene,cycloalkenyl, cycloalkenylene, cycloalkyne, cycloalkynyl,cycloalkynylene, heteroarene, heteroatyl, heterocycloalkane,heterocycloalkyl, heterocycloalkene, heterocycloalkenyl and spiroalkyl.

The term “cycloalkylene” or c ycloalky” or “cycloalkane” as used herein,means a monocyclic or bridged hydrocarbon ring system, The monocycliccycloalkyl is a carbocyclic ring system containing three to eight carbonatoms, zero heterostoms and zero double bonds. Examples of monocyclicring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. The monocyclic ring may contain one or twoalkylene bridges, each consisting of one, two, or three carbon atoms,each linking two non-adjacent carbon atoms of the ring system.Non-limiting examples of such bridged cycloalkyl ring systems includebicyclo[3.1.1]heptane, bicyclo[2.1.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane,tricyclo[3.3.1.0^(3.7)]nonane (octahydro-2,5-methanopentalene ornoradamantane), and tricyclo([3.3.1.1^(3.7)]decane (adamantane). Themonocyclic and bridged cycloalkyl can be attached to the parentmolecular moiety through any substitutable atom contained within thering system.

The term “cycloalkenylene,” or“cycloalkenyl” or “cycloalkene” as usedherein, means a monocyclic or a bridged hydrocarbon ring system. Themonocyclic cycloalkenyl has four-, five-, six-, seven- or eight carbonatoms and zero heteroatoms. The four-membered ring systems have onedouble bond, the five- or six-membered ring systems have one or twodouble bonds, and the seven- or eight-membered ring systems have one,two, or three double bonds. Representative examples of monocycliccycloalkenyl groups include, but are not limited to, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Themonocyclic cycloalkenyl ring may contain one or two alkylene bridges,each consisting of one, two, or three carbon atoms, each linking twonon-adjacent carbon atoms of the ring system. Representative examples ofthe bicyclic cycloalkenyl groups include, but are not limited to,4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl, and1,6-dihydro-pentalene. The monocyclic and bicyclic cycloalkenyl can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems.

The term “cycloalkyne,” or “cycloalkynyl,” or “cycloalkynylene,” as usedherein, means a monocyclic or a bridged hydrocarbon ring system. Themonocyclic cycloalkynyl has eight or more carbon atoms, zeroheteroatoms, and one or more triple bonds. The monocyclic cycloalkynylring may contain one or two alkylene bridges, each consisting of one,two, or three carbon atoms, each linking two non-adjacent carbon atomsof the ring system. The monocyclic and bridged cycloalkynyl can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems.

The term “heteroarene,” or “heteroaryl,” or “heteroarylene,” as usedherein, means a five-membered or six-membered aromatic ring having atleast one carbon atom and one or more than one independently selectednitrogen, oxygen or sulfur atom. The heteroarenes of this invention areconnected through any adjacent atoms in the ring, provided that propervalences are maintained. Representative examples of heteroaryl include,but are not limited to, furanyl (including, but not limited thereto,furan-2-yl), imidazolyl (including, but not limited thereto,1H-imidazol-1-yl), isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl,pyridinyl (e.g. pyridin-4-yl, pyridin-2-yl, pyridin-3-yl), pyridazinyl,pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl,thiazolyl, thienyl (including, but not limited thereto, thien-2-yl,thien-3-yl), triazolyl, and triazinyl.

The term “heterocycloalkane” or “heterocycloalkyl,” or“heterocycloalkylene,” as used herein, means monocyclic or bridgedthree-, four-, five-, six-, seven-, or eight-membered ring containing atleast one heteroatom independently selected from the group consisting ofO, N, and S and zero double bonds. The monocyclic and bridgedheterocycloalkane are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the rings. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized and the nitrogen atoms mayoptionally be quarternized. Representative examples of heterocycloalkanegroups include, but are not limited to, Representative examples ofheterocycloalkane groups include, but are not limited to, morpholinyl,tetrahydropyranyl, pyrrolidinyl, piperidinyl, dioxolanyl,tetrahydrofuranyl, thiomorpholinyl, dioxanyl, tetrahydrothienyl,tetrahydrothiopyranyl, oxetanyl, piperazinyl, imidazolidinyl, azetidine,azepanyl, aziridinyi, diazepanyl, dithiolanyl, dithianyl,isoxazolidinyl, isothiazolidinyl, oxadiazolidinyl, oxazolidinyl,pyrazolidinyl, tetrahydrothienyl, thiadiazolidinyl, thiazolidinyl,thiomorpholinyl, trithianyl, and trithianyl.

The term “heterocyclalkene,” or “heterocycloalkenyl,” or“heterocycloalkenylene,” as used herein, means monocyclic or bridgedthree-, four-, five, six-, seven-, or eight-membered ring containing atleast one heteroatom independently selected from the group consisting ofO, N, and S and one or more double bonds. The monocyclic and bridgedheterocycloalkene are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the rings. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized and the nitrogen atoms mayoptionally be quarternized. Representative exmaples of heterocycloalkenegroups include, but are not limited to, tetrahydrooxocinyl,1,4,5,6-tetrahydropyridazinyl, 1,2,3,6-tetrahydropyridinyl,dihydropyranyl, imidazolinl, isothiazolinyl, oxadiazolinyl,isoxazolinyl, oxazolinyl, pyranyl, pyrazolinyl, pyrrolinyl,thiadiazolinyl, thiazolinyl, and thiopyranyl.

The term “phenylene,” as used herein, means a divalent radical formed byremoval of a hydrogen atom from phenyl.

The term “spiroalkyl,” as used herein, means alkylene, both ends ofwhich are attached to the same carbon atom and is exemplified byC₂-spiroalkyl, C₃-spiroalkyl, C₄-spiroalkyl, C₅-spiroalkyl,C₆-spiroalkyl, C₇-spiroalkyl, C₈-spiroalkyl, C₉-spiroalkyl and the like.

The term “spiroheteroalkyl,” as used herein, means spiroalkyl have oneor two CH₂ moieties replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N.

The term “spiroheteroalkenyl,” as used herein, means spiroalkenyl havingone or two CH₂ moieties replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N and also means spiroalkenyl having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties replacedwith N.

The term, “spirocyclo,” as used herein, means two substituents on thesame carbon atom, that, together with the carbon atom to which they areattached, form a cycloalkane, heterocycloalkane, cycloalkene, orheterocycloalkene ring.

The term, “C₂-C₅-spiroalkyl,” as used herein, means C₂-spiroalkyl,C₃-spiroalkyl, C₄-spiroalkyl, and C₅-spiroalkyl.

The term “C₂-spiroalkyl,” as used herein, means eth-1,2-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₃-spiroalkyl,” as used herein, means prop-1,3-ylene both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₄-spiroalkyl,” as used herein, means but-1,4-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₅-spiroalkyl,” as used herein, means pent-1,5-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₆-spiroalkyl,” as used herein, means hex-1,6-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “NH protecting group,” as used herein, meanstrichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl,dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl,acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl,para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl,diphenylmethoxycarbonyl, 1,1-dimethylpropoxy-carbonyl,isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl,1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl,triphenyimethyl, 2-nitrophenylthio, methanesulfonyl,para-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene,2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene,2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene,cyclohexylidene. 2-ethoxycarbonylcyclohexylidene,2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene,3,3-dimethyl-5-oxycyclo-hexylidene, diphenylphosphoryl,dibenzylphosphoryl, 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl,trimethylsilyl, triethylsilyl, and triphenylsilyl.

The term “C(O)OH protecting group,” as used herein, means methyl, ethyl,n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl,naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl,para-methoxybenzyl, bis(para-methoxyphenyl)methyl, acetylmethyl,benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl,para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl,succmimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl,1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl,triethylsilyl, triisopropylsilyl, diethylisopropylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl,and tert-butylmethoxyphenylsilyl.

The term “OH or SH protecting group,” as used herein, meansbenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl,diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl,2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, S-benzythiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl,2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl,allyl, benzyl(phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl,diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl,2-(trimethylsilyl)ethoxymethyl 1-ethoxyethyl, methanesulfonyl,para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl,diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,diphenylmethylsilyl, and tert-butytmethoxyphenylsilyl.

Compounds

Geometric isomers may exist in the present compounds. Compounds of thisinvention may contain carbon-carbon double bonds or carbon-nitrogendouble bonds in the E or Z configuration, wherein the term “E”represents higher order substituents on opposite sides of thecarbon-carbon or carbon-nitrogen double bond and the term “Z” representshigher order substituents on the same side of the carbon-carbon orcarbon-nitrogen double bond as determed by the Cahn-Ingold-PrelogPriority Rules. The compounds of this invention may also exist as amixture of “E” and “Z” isomers. Substituents around a cycloalkyl orheterocycloalkyl are designated as being of cis or trans configuration.Furthermore, the invention contemplates the various isomers and mixturesthereof resulting from the disposal of substituents around an adamantanering system. Two substituents around a single ring within an adamantanering system are designated as being of Z or E relative configuration.For examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. leNoble J. Org. Chem. 1998, 63, 2758-2760 and E. L. Eliel, and S. H.Wilen, (1994 ) Stereochemistry of Organic Compounds, New York, N.Y.:John Wiley & Sons, Inc.

Comounds of this invention may contain asymmetrically substituted carbonatoms in the R or S configuration, in which the terms “R” or “S” are asdefined by the IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds havingasymmetrically substituted carbon atoms with equal amounts of R and Sconfiguarations are racemic at those carbon atoms. Atoms with an excessof one configuration over the other are assigned the configurationpresent in the higher amount, prefeably an excess of about 85%-90%, morepreferably an excess of about 95%-99%, and still more prefeably anexcess greater than about 99%. Accordingly, this invention includesracemic mixtures, relative and absolute stereoisomers, and mixtures ofrelative and absolute stereoisomers.

Compounds of this invention containing NH, C(O)OH, OH or SH moieties mayhave attached thereto prodrug-forming moieties. The prodrug-formingmoieties are removed by metabolic processes and release the compoundshaving the freed hydroxyl, amino or carboxylic acid in vivo. Prodrugsare useful for adjusting such pharmacokinetic properties of thecompounds as solubility and/or hydrophobicity, absorption in thegastrointestinal tract, bioavailability, tissue penetration, and rate ofclearance. An example of a compound with a prodrug-forming moiety is[3-chloro-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)-2-iminopyridin-1-(2H)-yl]methyldihydrogen phosphate (EXAMPLE 397), which is a prodrug of 2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide(EXAMPLE 318).

Isotope Enriched or Labeled Compounds

Compounds of the invention can exist in isotope-labeled or -enrichedform containing one or more atoms ahving an atomic mass or mass numberdifferent from the atomic mass or mass number most abnundantly found innature. Isotopes can be radioactive or non-radioactive isotopes.isotopes of atoms such as hydrogen,c arbon, phosphorous, sulfur,fluorine, chlorine, and iodine include, but are not limited to, ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, ¹⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Compounds thatcontain other isotopes of these and/or other atoms are within the scopeof this invention.

In another embodiment, the isotope-labeled compounds contain deuterium(²H), tritium (³H) or ¹⁴C isotopes. Isotope-labeled compounds of thisinvention can be prepared by the general methods well known to personshaving ordinary skill in the art. Such isotope-labeled compounds can beconveniently prepared by carrying out the procedures disclosed in theExamples disclosed herein and Schemes by substituting a readilyavailable isotope-labeled reagent for a non-labeled reagent. In someinstances, compounds may be treated with isotope-labeled reagents toexchange a normal atom with its isotope, for example, hydrogen fordeuterium can be exchanged by the action of a deuteric acid such asD₂SO₄/D₂O. In addition to the above, relevant procedures andintermediates are disclosed, for instance, in Lizondo, J et al., DrugsFut, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3),673(1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCTpublications WO1997010223 , WO2005099353 , WO1995007271, WO2006008754;U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421;7,514,068; 7,511,013; and US Patent Application Publication Nos,20090137457; 20090131485; 20090131363; 20090118238; 20090111840;20090105338; 20090103307; 20090105147; 20090093422; 20090088416; and20090082471, the methods are hereby incorporated by reference.

The isotope-labeled compounds of the invention may be used as standardsto determine the effectiveness of Bcl-2 inhibitors in binding assays.Isotope containing compounds have been used in pharmaceutical researchto investigate the in vivo metabolic fate of the compounds by evaluationof the mechanism of action and metabolic pathway of thenonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3,367-391 (1975)). Such metabolic studies are important in the design ofsafe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal., Advances in Drug Research Vol. 14, pp. 2-36, Academic press,London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut.,36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77,79-88 (1999).

In addition, non-radioactive isotope containing drugs, such asdeuterated drugs called “heavydrugs,” can be used for the treatment ofdiseases and conditions related to Bcl-2 activity. Increasing the amountof an isotope present in a compound above its natural abundance iscalled enrichment. Examples of the amount of enrichment include fromabout 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37,42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol%. Replacement of up to about 15% of normal atom with a heavy isotopehas been effected and maintained for a period of days to weeks mmammals,including rodents and dogs, with minimal observed adverse effects(Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson JF, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al. Am. J.Physiol. 1961 201: 357). Acute replacement of as high as 15%-23% inhuman fluids with deuterium was found not to cause toxicity (BlagojevicN et al. in “Dosimetry & Treatment Planning foir Neutron CaptureTherapy”, Zamenhof R, Solares G and Harling O Eds. 1994. AdvancedMedical Publishing, Madison Wis. pp. 125-134; Diabetes Metab. 23: 251(1997)).

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction. While some of the physical properities of astable isotope-labeled molecule are different from those of theunlabeled one, the chemical and biological properties are the same, withone important exception: because of the increased mass of the heavyisotope, any bound involving the heavy isotope and another atom will bestronger than the same bond between the light isotope and that atom.Accordingly, the incorporation of an isotope at a site of metabolism orenzymatic transofrmation will slow said reactions potentially alteringthe pharmcokinetic profile or efficacy relative to the non-isotopiccompound.

Amides, Esters and Prodrugs

Prodrugs are derivatives of an active drug designed to ameliorate someidentified, undesirable physical or biological property. The physicalproperties are usually solubility (too much or not enough lipid oraqueous solubility) or stability related, while problematic biologicalproperties include too rapid metabolism or poor bioavailability whichitself may be related to a physicochemical property.

Prodrugs are usually prepared by: a) formation of ester, hemi esters,carbonate esters, nitrate esters, amides, hydroxamic acids, carbamates,imines, Mannich bases, phosphates, phosphate esters, and enamines of theactive drug, b) functionalizing the drug with azo, glycoside, peptide,and ether functional groups, c) use of aminals, hemi-aminals, polymers,salts, compleses, phosphoramides, acetals, hemiacetals, and ketal formsof the drug. For example, see Andrejus Korolkovas's, “Essentials ofMedicinal Chemistry”, John Wiley-Interscience Publications, John Wileyand Sons, New York (1988), pp. 97-118, which is incorporated in itsentirety by reference herein.

Esters can be prepared from substrates of formula (I) containing eithera hydroxyl group or a carboxy group by general methods known to personsskilled in the art. The typical reactions of these compounds aresubstitutions replacing one of the heteroatoms by another atom, forexample:

Amides can be prepared from substrates of formula (I) containing eitheran amino group or a carboxy group in similar fashion. Esters can alsoreact with amines or ammonia to form amides.

Another way to make amides from compounds of formula (I) is to heatcarboxylic acids and amines together.

In Schemes 2 and 3 above, R and R′ are independently substrates offormula (I), alkyl or hydrogen.

Suitable groups for for A¹, B¹, D¹, E¹, Y¹, L¹, Z^(1A), Z^(2A), Z¹, Z²,and Z³ in compounds of Formula (I) are independently selected. Thedescribed embodiments of the present invention may be combined. Suchcombination is contemplated and within the scope of the presentinvention. For example, it is contemplated that the embodiments for anyof A¹, B¹, D¹, E¹, Y¹, L¹, Z^(1A), Z^(2A), Z¹, Z², and Z³ can becombined with embodiments defined for any other of A¹, B¹, D¹, E¹, Y¹,L¹, Z^(1A), Z^(2A), Z¹, Z², and Z³.

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,which are useful as inhibitors of anti-apoptotic Bcl-2 proteins, thecompounds having Formula (I)

wherein

-   A¹ is N or C(A²);

A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, SO₂R¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷,C(O)NH₂, C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷, or NHSO₂R¹⁷; or

E¹ and Y¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², B¹, and D¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², D¹, and E¹ are independendy selected H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹,C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹,NR¹C(O)¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂,NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹,NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH,C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹,NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H,CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂, or C(O)OR^(1A); or

A² and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

D¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂, or C(O)OR^(1A); or

A² and D¹, together with the atoms to which they are attached, arebenzene, naphthalene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

B¹, and E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is cycloalkyl, cycloalkenyl ar cycloalkynyl;

R² is phenyl, which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷,SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(10A);R^(10A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R¹¹ is alkyl, alkenyl or alkynyl, each of which isunsubstituted or substituted with one or two or three of independentlyselected R¹², OR¹², SR¹², S(O)R¹², SO₂R¹², C(O)R¹², C(O)R¹², OC(O)R¹²,OC(O)OR¹², NH₂NHR¹², N(R¹²)₂, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹²,NR¹²S(O)₂R¹², NHC(O)OR¹², NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹²,NHC(O)N(R¹²)₂, NR¹²C(O)NHR¹², NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹²,C(O)N(R¹²)₂, C(O)NHOH, C(O)NHOR¹², C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂,SO₂NHR¹², SO₂N(R¹²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹², C(N)N(R¹²)₂,CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl,Br or I;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(14A); R^(14A) is cycloalkane, cycloakene, heterocycloalkane orheterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(20A);R^(20A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R²²,OR²², SR²², S(O)R²², SO₂R²², C(O)R²², CO(O)R²², OC(O)R²², OC(O)OR²²,NH₂, NHR²², N(R²²)₂, NHC(O)R²², NR²²C(O)R²², NHS(O)₂R²², NR²²S(O)₂R²²,NHC(O)OR²², NR²²C(O)OR²², NHC(O)NH₂, NHC(O)NHR²², NHC(O)N(R²²)₂,NR²²C(O)NHR²², NR²²C(O)N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂,C(O)NHOH, C(O)NHOR²², C(O)NHSO₂R²², C(O)NR²²SO₂R²², SO₂NH₂, SO₂NHR²²,SO₂N(R²²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR²², C(N)N(R²²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloakane orheterocycloalkene;

R²⁴ is heteroarene, which is unfused or fused with benzene, heteroareneor R^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(25A);R^(25A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

Z¹ is R²⁶ or R²⁷;

Z² is R²⁸, R²⁹ or R³⁰;

Z^(1A) and Z^(2A) are both absent or are taken together to form CH₂,CH₂CH₂ or Z^(12A);

Z^(12A) is C₂-C₆-alkylene having one or two CH₂ moieties replaced by NH,N(CH₃), S, S(O) or SO₂;

L¹ is R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, C(O)R³⁷, CO(O)R³⁷, OC(O)R³⁷,OC(O)OR³⁷, NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO₂R³⁷, SO₂NH,SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R²⁶ is phenylene, which is unfused or fused with benzene or heteroareneor R^(26A); R^(26A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁷ is heteroarylene, which is unfused or fused with benzene orheteroarene or R^(27A); R^(27A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²⁸ is phenylene, which is unfused or fused with benzene, heteroarene orR^(28A); R^(28A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with benzene orheteroarene or R^(29A); R^(29A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkylene, cycloalkenylene, heterocycloalkylene orheterocycloalkenylene, each of which is unfused or fused with benzene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^(37A);

R^(37A) is alkylene, alkenylene, or alkynylene, each of which isunsubstituted or substituted with one or two or three independentlyselected R^(37B), OR^(37B), SR^(37B), S(O)R^(37B), SO₂R^(37B),C(O)R^(37B), CO(O)R^(37B), OC(O)R^(37B), OC(O)OR^(37B), NH₂, NHR^(37B),N(R^(37B))₂, NHC(O)R^(37B), NR^(37B)C(O)R^(37B), NHS(O)₂R^(37B),NR^(37B)S(O)₂R^(37B), NHC(O)OR^(37B), NR^(37B)C(O)OR^(37B), NHC(O)NH₂,NHC(O)NHR^(37B), NHC(O)N(R^(37B))₂, NR^(37B)C(O)NHR^(37B),NR^(37B)C(O)N(R^(37B))₂, C(O)NH₂, C(O)NHR^(37B), C(O)N(R^(37B))₂,C(O)NHOH, C(O)NHOR^(37B), C(O)NHSO₂R^(37B), C(O)NR^(37B)SO₂R^(37B),SO₂NH₂, SO₂NHR^(37B), SO₂N(R^(37B))₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR^(37B), C(N)N(R^(37B))₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃,CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl Br and I substituents;

R^(37B) is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(40A);R^(40A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the moieties represented by R²⁶ and R²⁷ are substituted (i.e.,if Z^(1A) and Z^(2A) are absent) or further substituted (i.e., if Z^(1A)and Z^(2A) are present) with one or two or three or four ofindependently selected R⁴¹, OR⁴¹, SR⁴¹, S(O)R⁴¹, SO₂R⁴¹, C(O)R⁴¹,CO(O)R⁴¹, OC(O)R⁴¹, OC(O)OR⁴¹, NH₂, NHR⁴¹, N(R⁴¹)₂, NHC(O)R⁴¹,NR⁴¹C(O)R⁴¹, NHS(O)₂R⁴¹, NR⁴¹S(O)₂R⁴¹, NHC(O)OR⁴¹, NR⁴¹C(O)OR⁴¹,NHC(O)NH₂, NHC(O)NHR⁴¹, NHC(O)N(R⁴¹)₂, NR⁴¹C(O)NHR⁴¹, NR⁴¹C(O)N(R⁴¹)₂,C(O)NH₂, C(O)NHR⁴¹, C(O)N(R⁴¹)₂, C(O)NHOH, C(O)NHOR⁴¹, C(O)NHSO₂R⁴¹,C(O)NR⁴¹SO₂R⁴¹, SO₂NH₂, SO₂NHR⁴¹, SO₂N(R⁴¹)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁴¹, C(N)N(R⁴¹)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl, which is unfused or fused with benzene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁴⁶,OR⁴⁶, SR⁴⁶, S(O)R⁴⁶, C(O)R⁴⁶, CO(O)R⁴⁶, OC(O)R⁴⁶, OC(O)OR⁴⁶, NH₂, NHR⁴⁶,N(R⁴⁶)₂, NHC(O)R⁴⁶, NR⁴⁶C(O)R⁴⁶, NHS(O)₂R⁴⁶, NR⁴⁶S(O)₂R⁴⁶, NHC(O)OR⁴⁶,NR⁴⁶C(O)OR⁴⁶, NHC(O)NH₂, NHC(O)NHR⁴⁶, NHC(O)N(R⁴⁶)₂, NR⁴⁶C(O)NHR⁴⁶,NR⁴⁶C(O)N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, C(O)NHOH, C(O)NHOR⁴⁶,C(O)NHSO₂R⁴⁶, C(O)NR⁴⁶SO₂R⁴⁶, SO₂NH₂, SO₂NHR⁴⁶, SO₂N(R⁴⁶)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁴⁶, C(N)N(R⁴⁶)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁴⁶ is alkyl, alkenyl, alkynyl, R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl, which is unfused or fused with benzene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(48A); R^(48A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(49A);R^(49A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the moieties represented by R⁴², R^(42A), R⁴³, R^(43A), R⁴⁴,R^(44A), R⁴⁷, R^(47A), R⁴⁸, R^(48A), R⁴⁹, and R^(49A) are independentlysubstituted with one or two or three or four of independently selectedR⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰, CO(O)R⁵⁰, OC(O)R⁵⁰,OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, NHC(O)R⁵⁰, NR⁵⁰C(O)R⁵⁰, NHS(O)₂R⁵⁰,NR⁵⁰S(O)₂R⁵⁰, NHC(O)OR⁵⁰, NR⁵⁰C(O)OR⁵⁰, NHC(O)NH₂, NHC(O)NHR⁵⁰,NHC(O)N(R⁵⁰)₂, NR⁵⁰C(O)NHR⁵⁰, NR⁵⁰C(O)N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰,C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁰SO₂R⁵⁰, SO₂NH₂,SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂,CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl,Br or I;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(51A); R^(51A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(52A); R^(52A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heteracycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(53A);R^(53A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁵⁵,OR⁵⁵, SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, C(O)R⁵⁵, CO(O)R⁵⁵, OC(O)R⁵⁵, OC(O)OR⁵⁵,NH₂, NHR⁵⁵, N(R⁵⁵)₂, NHC(O)R⁵⁵, NR⁵⁵C(O)R⁵⁵, NHS(O)₂R⁵⁵, NR⁵⁵S(O)₂R⁵⁵,NHC(O)OR⁵⁵, NR⁵⁵C(O)OR⁵⁵, NHC(O)NH₂, NHC(O)NHR⁵⁵, NHC(O)N(R⁵⁵)₂,NR⁵⁵C(O)NHR⁵⁵, NR⁵⁵C(O)N(R⁵⁵)₂, C(O)NH₂, C(O)NHR⁵⁵, C(O)N(R⁵⁵)₂,C(O)NHOH, C(O)NHOR⁵⁵, C(O)NHSO₂R⁵⁵, C(O)NR⁵⁵SO₂R⁵⁵, SO₂NH₂, SO₂NHR⁵⁵,SO₂N(R⁵⁵)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁵, C(N)N(R⁵⁵)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

wherein each foregoing cyclic moiety is independently unsubstituted,further unsubstituted, substituted or further substituted with one ortwo or three or four or five of independently selected R^(57A), R⁵⁷,OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, OC(O)R⁵⁷, OC(O)OR⁵⁷,NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷, NR⁵⁷C(O)R⁵⁷, NHS(O)₂R⁵⁷, NR⁵⁷S(O)₂R⁵⁷,NHC(O)OR⁵⁷, NR⁵⁷C(O)OR⁵⁷, NHC(O)NH₂, NHC(O)NHR⁵⁷, NHC(O)N(R⁵⁷)₂,NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷)₂, C(O)NH₂, C(O)NHR⁵⁷, C(O)N(R⁵⁷)₂,C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷, C(O)NR⁵⁷SO₂R⁵⁷, SO₂NH₂, SO₂NHR⁵⁷,SO₂N(R⁵⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁷, C(N)N(R⁵⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R^(57A) is spirocyclyl;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR⁵⁸; R⁵⁸A is cycloalkane, cycloalkane, heterocycloalkane orheterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R⁵⁹A; R^(59A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(60A);R^(60A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶²,OR⁶², SR⁶², S(O)R⁶², SO₂R⁶², C(O)R⁶², CO(O)R⁶², OC(O)R⁶², OC(O)OR⁶²,NH₂, NHR⁶², N(R⁶²)₂, NHC(O)R⁶², NR⁶²C(O)R⁶², NHS(O)₂R⁶², NR⁶²S(O)₂R⁶²,NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH₂, NHC(O)NHR⁶², NHC(O)N(R⁶²)₂,NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)₂,C(O)NHOH, C(O)NHOR⁶², C(O)NHSO₂R⁶², C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NHR⁶²,SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶², C(N)N(R⁶²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(63A); R^(63A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R⁶⁴A; R^(64A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(65A);R^(65A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁶ is alkyl, alkenyl or alkenyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶⁷,OR⁶⁷, SR⁶⁷, S(O)R⁶⁷, SO₂R⁶⁷, C(O)R⁶⁷, CO(O)R⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷,NH₂, NHR⁶⁷, N(R⁶⁷)₂, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷,NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂,C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NHR⁶⁷,SO₂N(R⁶⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R^(57A), R⁵⁸, R⁵⁹, R⁶⁰, R⁶³, R⁶⁴,R⁶⁵, and R⁶⁷ are unsubstituted or substituted with one or two or threeor four of independently selected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸, SO₂R⁶⁸,C(O)R⁶⁸, CO(O)R⁶⁸, OC(O)R⁶⁸, OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂, NHC(O)R⁶⁸,NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸, NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸, NR⁶⁸C(O)OR⁶⁸,NHC(O)NH₂, NHC(O)NHR⁶⁸, NHC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸, NR⁶⁸C(O)N(R⁶⁸)₂,C(O)NH₂, C(O)NHR⁶⁸, C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸, C(O)NHSO₂R⁶⁸,C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂, SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl which is unfused or fused with benzene, heteroarene orR^(69A); R^(69A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(70A); R^(70A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(71A);R^(71A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷² is alkyl, alkenyl or alkenyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁷³,OR⁷³, SR⁷³, S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, CO(O)R⁷³, OC(O)R⁷³, OC(O)OR⁷³,NH₂, NHR⁷³, N(R⁷³)₂, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³,NHC(O)OR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂,NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂,C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³,SO₂N(R⁷³)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

the moieties represented by R⁶⁹, R⁷⁰ , and R⁷¹ are unsubstituted orsubstituted with one or two or three or four of independently selectedNH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, OH,(O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I.

Another embodiment of this invention pertains to compounds of Formula(I), wherein

A¹ is N or C(A²);

A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F,Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(1A);

E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂ N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, SO₂R¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷,C(O)NH₂, C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷, or NHSO₂R¹⁷; or

E¹ and Y¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², B¹, and D¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, CO(O)R¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂), NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂ N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane, or heterocycloalkene; and

A², D¹, and E¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, CO(O)R¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂), NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

A² and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

D¹, E¹, and Y¹are independently selected H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹,C(O)R¹, CO(O)R¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹,NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂,NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹,NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂), NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH,C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂ NHR¹,NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H,CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

A² and D¹, together with the atoms to which they are attached, arebenzene, naphthalene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

B¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, CO(O)R¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂), NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R⁴A; R⁴Ais cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)CNH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷,SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(10A);R^(10A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R¹²,OR¹², SR¹², S(O)R¹², SO₂R¹², C(O)R¹², CO(O)R¹², OC(O)R¹², OC(O)OR¹²,NH₂, NHR¹², N(R¹²)₂, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹², NR¹²S(O)₂R¹²,NHC(O)OR₂, NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹², NHC(O)N(R¹²)₂,NR¹²C(O)NHR¹², NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂,C(O)NHOH, C(O)NHOR¹², C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂,SO₂NHR¹²,SO₂N(R¹²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹², CN(N)N(R¹²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br, I;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(14A); R^(14A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(20A);R^(20A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²¹ is alkyl, aikenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R²²,OR²², SR²², S(O)R²², SO₂R²², C(O)R²², CO(O)R²², OC(O)R²², OC(O)OR²²,NH₂, NHR²², N(R²²)₂, NHC(O)R²², NR²²C(O)R²², NHS(O)₂R²², NR²²S(O)₂R²²,NHC(O)OR²², NR²²C(O)OR²², NHC(O)NH₂, NHC(O)NHR²², NHC(O)N(R²²⁾ ₂,NR²²C(O)NHR²², NR²²C(O)N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂,C(O)NHOH, C(O)NHOR²², C(O)NHSO₂R²², C(O)NR²²SO₂R²², SO₂NH₂, SO₂NHR²²,SO₂N(R²²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR²², C(N)N(R²²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R²² is R²³, R²⁴ or R²⁵;

R²² is phenyl, which is unfused or fused with benzene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene, which is unfused or fused with benzene, heteroareneor R^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R^(25A);R^(25A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

Z¹ is R²⁶ or R²⁷;

Z² is R²⁸, R²⁹ or R³⁰;

Z^(1A) and Z^(2A) are both absent or are taken together to form CH₂,CH₂CH₂ or Z^(12A);

Z^(12A) is C₂-C₆-alkylene having one or two CH₂ moieties replaced by NH,N(CH₃), S, S(O) or SO₂;

L¹ is a R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, C(O)R³⁷, CO(O)R³⁷, OC(O)R³⁷,OC(O)OR³⁷, NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO₂R³⁷, SO₂NH,SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R²⁶ is phenylene, which is unfused or fused with benzene or heteroareneor R^(26A); R^(26A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁷ is heteroarylene, which is unfused or fused with benzene orheteroarene or R^(27A); R^(27A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²⁸ is phenylene, which is unfused or fused with benzene, heteroarene orR^(28A); R^(28A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with benzene orheteroarene or R^(29A); R^(29A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkylene, cycloalkenylene, heterocycloalkylene orheterocycloalkenylene, each of which is unfused or fused with benzene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^(37A);

R^(37A) is alkylene, alkenylene, or alkynylene, each of which isunsubstituted or substituted with one or two or three independentlyselected R^(37B), OR^(37B), SR^(37B), S(O)R^(37B), SO₂R^(37B),C(O)R^(37B), CO(O)R^(37B), OC(O)R^(37B), OC(O)OR^(37B), NH₂, NHR^(37B),N(R^(37B))₂, NHC(O)R^(37B), NR^(37B)C(O)R^(37B), NHS(O)₂R^(37B),NR^(37B)S(O)₂R^(37B), NHC(O)OR^(37B), NR^(37B)C(O)OR^(37B), NHC(O)NH₂,NHC(O)NHR^(37B), NHC(O)N(R^(37B))₂, NR^(37B)C(O)NHR^(37B),NR^(37B)C(O)N(R^(37B))₂, C(O)NH₂, C(O)NHR^(37B), C(O)N(R^(37B))₂,C(O)NHOH, C(O)NHOR^(37B), C(O)NHSO₂R^(37B), C(O)NR^(37B)SO₂R^(37B),SO₂NH₂, SO₂NHR^(37B), SO₂N(R^(37B))₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR^(37B), C(N)N(R^(37B))₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃,CF₂CF₃OCF₃, OCF₂CF₃F, Cl, Br and I substituents;

R^(37B) is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(40A);R^(40A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the moieties represented by R²⁶ and R²⁷ are substituted wtihOR⁴¹;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl, which is unfused or fused with benzene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁴⁶,OR⁴⁶, SR⁴⁶, S(O)R⁴⁶, C(O)R⁴⁶, CO(O)R⁴⁶, OC(O)R⁴⁶, OC(O)OR⁴⁶, NH₂, NHR⁴⁶,N(R⁴⁶)₂, NHC(O)R⁴⁶, NR⁴⁶C(O)R⁴⁶, NHS(O)₂R⁴⁶, NR⁴⁶S(O)₂R⁴⁶, NHC(O)OR⁴⁶,NR⁴⁶C(O)OR⁴⁶, NHC(O)NH₂, NHC(O)NHR⁴⁶, NHC(O)N(R⁴⁶)₂, NR⁴⁶C(O)NHR⁴⁶,NR⁴⁶C(O)N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, C(O)NHOH, C(O)NHOR⁴⁶,C(O)NHSO₂R⁴⁶, C(O)NR⁴⁶SO₂R⁴⁶, SO₂NH₂, SO₂NHR⁴⁶, SO₂N(R⁴⁶)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁴⁶, C(N)N(R⁴⁶)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁴⁶ is alkyl, alkenyl, alkynyl, R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl, which is unfused or fused with benzene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(48A); R^(48A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(49A);R^(49A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the moieties represented by R⁴², R^(42A), R⁴³, R^(43A), R⁴⁴,R^(44A), R⁴⁷, R^(47A), R⁴⁸, R^(48A), R⁴⁹, and R^(49A) are independentlysubstituted with one or two or three or four of independently selectedR⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰, CO(O)R⁵⁰, OC(O)R⁵⁰,OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, NHC(O)R⁵⁰, NR⁵⁰C(O)R⁵⁰, NHS(O)₂R⁵⁰,NR⁵⁰S(O)₂R⁵⁰, NHC(O)OR⁵⁰, NR⁵⁰C(O)OR⁵⁰, NHC(O)NH₂, NHC(O)NHR⁵⁰,NHC(O)N(R⁵⁰)₂, NR⁵⁰C(O)NHR⁵⁰, NR⁵⁰C(O)N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰,C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁰SO₂R⁵⁰, SO₂NH₂,SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, C(O)H, C(O)OH, C(N)NH₂, CCN)NHR⁵⁰, C(N)N(R⁵⁰)₂,CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl,Br or I;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(51A); R^(51A) is cycloalkane, cycloalkene, heterocycloalkene orheterocycloalkene;

R⁵² is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(52A); R^(52A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(53A);R^(53A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁵⁵,OR⁵⁵, SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, C(O)R⁵⁵, CO(O)R⁵⁵, OC(O)R⁵⁵, OC(O)OR⁵⁵,NH₂, NHR⁵⁵, N(R⁵⁵)₂, NHC(O)R⁵⁵, NR⁵⁵C(O)R⁵⁵, NHS(O)₂R⁵⁵, NR⁵⁵S(O)₂R⁵⁵,NHC(O)OR⁵⁵, NR⁵⁵C(O)OR⁵⁵, NHC(O)NH₂, NHC(O)NHR⁵⁵, NHC(O)N(R⁵⁵)₂,NR⁵⁵C(O)NHR⁵⁵, NR⁵⁵C(O)N(R⁵⁵)₂, C(O)NH₂, C(O)NHR⁵⁵, C(O)N(R⁵⁵)₂,C(O)NHOH, C(O)NHOR⁵⁵, C(O)NHSO₂R⁵⁵, C(O)NR⁵⁵SO₂R⁵⁵, SO₂NH₂, SO₂NHR⁵⁵,SO₂N(R⁵⁵)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁵, C(N)N(R⁵⁵)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

wherein each foregoing cyclic moiety is independently unsubstituted,further unsubstituted, substituted or further substituted with one ortwo or three or four or five of independently selected R^(57A), R⁵⁷,OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, OC(O)R⁵⁷, OC(O)OR⁵⁷,NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷, NR⁵⁷C(O)R⁵⁷, NHSO₂R⁵⁷, NR⁵⁷S(O)₂R⁵⁷,NHC(O)OR⁵⁷, NR⁵⁷C(O)QR⁵⁷, NHC(O)NH₂, NHC(O)NHR⁵⁷, NHC(O)N(R⁵⁷)₂,NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷⁾ ₂, C(O)NH₂, C(O)NHR⁵⁷, C(O)N(R⁵⁷)₂,C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷, C(O)NR⁵⁷SO₂R⁵⁷, SO₂NH₂, SO₂NHR⁵⁷,SO₂N(R⁵⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁷, C(N)NH(R⁵⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R^(57A) is spirocyclyl;

R⁵⁸ is phenyl, which is unfused or fused with benzene, heteroarene orR^(58A); R^(58A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(59A); R^(59A) is cycloalkane, cycloalkene, heterecycloalkane orheterocycloalkene;

R⁶⁰is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(60A);R^(60A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶²,OR⁶², SR⁶², S(O)R⁶², SO₂R⁶², C(O)R⁶², CO(O)R⁶², C(O)R⁶², OC(O)OR⁶², NH₂,NHR⁶², N(R⁶²)₂, NHC(O)R⁶², NR⁶²C(O)R⁶², NHSO₂R⁶², NR⁶²S(O)₂R⁶²,NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH₂, NHC(O)NHR⁶², NHC(O)N(R⁶²⁾ ₂,NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)₂,C(O)NHOH, C(O)NHOR⁶², C(O)NHSO₂R⁶², C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NHR⁶²,SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶²), C(N)N(R⁶²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₃, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, Cl, Br or I;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with benzene, heteroarene orR^(63A); R^(63A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(64A); R^(64A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(65A);R^(65A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁶ is alkyl, alkenyl or alkenyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶⁷,OR⁶⁷, SR⁶⁷, S(O)R⁶⁷, SO₂R⁶⁷, C(O)R⁶⁷, CO(O)R⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷,NH₂, NHR⁶⁷, N(R⁶⁷)₂, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷,NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂,C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NHR⁶⁷,SO₂N(R⁶⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the moieties represented by R^(57A), R⁵⁸, R⁵⁹, R⁶⁰, R⁶³, R⁶⁴,R⁶⁵, and R⁶⁷ are unsubstituted or substituted with one or two or threeor four of independently selected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸, SO₂R⁶⁸,C(O)R⁶⁸, CO(O)R⁶⁸, OC(O)R⁶⁸, OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂, NHC(O)R⁶⁸,NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸, NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸, NR⁶⁸C(O)OR⁶⁸,NHC(O)NH₂, NHC(O)NHR⁶⁸, NHC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸, NR⁶⁸C(O)N(R⁶⁸)₂,C(O)NH₂, C(O)NHR⁶⁸, C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸, C(O)NHSO₂R⁶⁸,C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂, SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl, which is unfused or fused with benzene, heteroarene orR^(69A); R^(69A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with benzene, heteroareneor R^(70A); R^(70A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(71A);R^(71A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷² is alkenyl or alkenyl, each of which is unsnbstituted or substitutedwith one or two or three of independently selected R⁷³, OR⁷³, SR⁷³,S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, CO(O)R⁷³, OC(O)R⁷³, OC(O)OR⁷³, NH₂, NHR⁷³,N(R⁷³)₂, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³, NHC(O)OR⁷³,NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂, NR⁷³C(O)NHR⁷³,NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂, C(O)NHOH, C(O)NHOR⁷³,C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³, SO₂N(R⁷³)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁷³ is alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

the moieties represented by R⁶⁹, R⁷⁰, and R⁷¹ are unsbustituted orsubstituted with one or two or three or four of independently selectedNH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, OH,(O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃s F, Cl, Br or I.

In one embodiment of Formula (I), A¹ is N. In another embodiment ofFormula (I), A¹ is C(A²). In another embodiment of Formula (I), A¹ isC(A²); and A² is H.

In one embodiment of Formula (I), B¹ is OR¹, or NHR¹. In anotherembodiment of Formula (I), A¹ is C(A²); A² is H; and B¹ is NHR¹. Inanother embodiment of Formula (I), A¹ is C(A²); A² is H; and B¹ is OR¹.

In one embodiment of Formula (I), D¹ H. In another embodiment of Formula(I), A¹ is C(A²); A² is H; and B¹ is NHR¹; and D¹ is H. In anotherembodiment of Formula (I), A¹ is C(A²); A² is H; B¹ is OR¹; and D¹ is H.

In one embodiment of Formula (I), E¹ is H. In another embodiment ofFormula (I), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; and E¹ is H. Inanother embodiment of Formula (I), A¹ is C(A²); A² is H; B¹ is OR¹; D¹is H; and E¹ is H.

In one embodiment of Formula (I), Y¹ is H, CN, NO₂, F, Cl, Br, CF₃, R¹⁷,or SO₂R¹⁷. In one embodiment of Formula (I), Y¹ is NO₂. In anotherembodiment of Formula (I), Y¹ is Cl. In another embodiment of Formula(I), Y¹ is SO₂R¹⁷; wherein R¹⁷ is as defined herein. In anotherembodiment of Formula (I), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl. Inanother embodiment of Formula (I), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl. Inanother embodiment of Formula (I), A¹ is C(A²); A² is H; and B¹ is NHR¹;D¹ is H; E¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl oralkynyl. In another embodiment of Formula (I), A¹ is C(A²); A² is H; B¹is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂. In another embodiment ofFormula (I), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹is SO₂R¹⁷, wherein R¹⁷ is alkyl substituted with three F. In anotherembodiment of Formula (I), A¹ is C(A²); A² is H; B¹ is OR¹; D¹ is H; E¹is H; and Y¹ is Cl.

In one embodiment of Formula (I), R¹ is R¹ is R⁴ or R⁵. In oneembodiment of Formula (I), R¹ is R⁴. In one embodiment of Formula (I),R¹ is R⁵. In one embodiment of Formula (I), R¹ is R⁴; and R⁴ iscycloalkyl, or heterocycloalkyl. In one embodiment of Formula (I), R¹ isR⁴; and R⁴ is cycloalkyl. In one embodiment of Formual (I), R¹ is R⁴;and R⁴ is heterocycloalkyl.

In one embodiment of Formula (I), R¹ is R⁴ ; and R⁴ is cycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is substituted as defined herein. In another embodimentof Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is substituted with R⁵⁷, NHR⁵⁷, or N(R⁵⁷)₂. In another embodimentof Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkylring is cyclohexyl; and wherein the cyclohexyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (I) R¹ is R⁴; R⁴iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; and R⁶⁰heterocycloalkyl. In another embodiment of Formula (I), R¹ is R⁴; R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl orpiperazinyl. In another embodiment of Formula (I), R¹ is R⁴; and R⁴ iscycloalkyl; wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂. Inanother embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexylring is substituted with N(R⁵⁷)₂. In another embodiment of Formula (I),R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring iscyclohexyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)₂,R⁵⁷ is R⁶⁰, and R⁶¹ alkyl which is unsubstituted. In another embodimentof Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is cyclohexyl; and wherein the cyclohexyl ring is substituted withN(R⁵⁷)₂, R⁵⁷ is R⁶⁰, and R⁶¹ is cycloalkyl which is unsubstituted. Inanother embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is substituted with NHR⁵⁷. In anotherembodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with NHR⁵⁷. In another embodiment of Formula (I), R¹ is R⁴;and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; andwherein the cyclohexyl ring is substituted with NHR⁵⁷, R⁵⁷ is R⁶⁰, andR⁶¹ is heteroeycloalkyl which is unsubstituted.

In one embodiment of Formula (I), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (I), R¹ is R⁴; and R⁴ is heterocycloalkyl; whereinthe heterecycloalkyl ring is substituted as defined herein. In anotherembodiment of Formula (I), R¹ is R⁴; and R⁴ is heterocycloalkyl; whereinthe heterocycloalkyl ring is substituted with R⁵⁷. In another embodimentof Formula (I), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl; and wherein the heterocycloalkyl ring is substituted withone or two or three or four or five more R⁵⁷; SO₂R⁵⁷, or OH, and R⁵⁷ isR⁶⁰ and R⁶¹. In another embodiment of Formula (I), R¹ is R⁴; R⁴ isheterocycfloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷;R⁵⁷is R⁶⁰ or R⁶¹; R⁶⁰ is cycloalkyl or heterocycloalkyl; and R⁶¹ isalkyl. In another embodiment of Formula (I), R¹ is R⁴; R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl,pyrrolinyl, morpholinyhl, or piperizinyl; ring is substituted with R⁵⁷;R⁵⁷is R⁶⁰; R⁶⁰ is heterocycloalkyl, wherein the heterocycloalkyl istetrahydropyranyl or oxetanyl. In another embodiment of Formula (I), R¹is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring ispiperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein thepiperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring issubstituted with R⁵⁷; R⁵⁷is R⁶⁰; R⁶⁰ is cycloalkyl, wherein thecycloalkyl is cyclopropyl or cyclopentyl. In another embodiment ofFormula (I), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinhyl, orpiperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl ring is substituted with one or two or three or four or fiveR⁵⁷; R⁵⁷is R⁶¹; R⁶¹ is alkyl; and the alkyl is C₁-alkyl, C₂-alkyl, orC₃-alkyl. In another embodiment of Formula (I), R¹ is R⁴; R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one ortwo or three or four or five R⁵⁷; R⁵⁷is R⁶¹; R⁶¹ is alkyl; and the alkylis C₁-alkyl, C₂-alkyl, or C₃-alkyl; wherein the C₁-alkyl, C₂-alkyl, orC₃-alkyl are unsubstituted or substituted.

In one embodiment of Formula (I), R¹ is R³; R⁵ is alkyl which isunsubstituted or substituted. In one embodiment of Formula (I), R¹ isR³; R⁵ is alkyl which is unsubstituted or substituted with R⁷, OR⁷,N(R⁷)₂, or OH.

In one embodiment of Formula (I), R⁷ is R¹⁰ or R¹¹ which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (I), R⁷ is R¹⁰ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (I), R⁷ is R¹¹ which isunsubstituted or substituted as defined herein.

In one embodiment of Formula (I), R¹⁰ is cycloalkyl or heterocycloalkylwhich are unsubstituted or substituted as defined herein. In anotherembodiment of Formula (I), R¹⁰ is heterocycloalkyl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (I), R¹⁰ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,dioxanyl, piperidinyl, piperizinyl, or pyrrolidinyl, which aresubstituted or substituted as defined herein. In another embodiment ofFormula (I), R¹⁰ is tetrahydropyranyl, which is unsubstituted orsubstituted as defined herein. In another embodiment of Formula (I), R¹⁰is morpholinyl, which is unsubstituted or substituted as defined herein.In another embodiment of Formula (I), R¹⁰ is cycloalkyl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (I), R¹⁰ is cyclohexyl which is unsubstituted or substituted asdefined herein.

In one embodiment of Formula (I), R¹¹ is alkyl which is unsubstituted.In another embodiment of Formula (I), R¹¹ is methyl, which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (I), R¹¹ is alkyl, which is substituted as defined herein. Inanother embodiment of Formula (I), R¹¹ is alkyl, which is substitutedwith OR¹², R¹² is R¹⁶, and R¹⁶ is alkyl.

Another embodiment of this invention pertains to compounds of Formula(I), wherein

A¹ is N or C(A 2);

A² is H;

B¹ is OR¹, NHR¹;

D¹ is H;

E¹ is H; and

Y¹ is H, CN, NO₂, F, Cl, Br, CF₃, R¹⁷, or SO₂R¹⁷;

R¹ is R⁴ or R⁵;

R¹ is cycloalkyl, or heterocycloalkyl;

R⁵ is alkyl or alkynyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R⁷, OR⁷, N(R⁷)₂, OH,F, Cl, Br or I;

R⁷ is R¹⁰ or R¹¹;

R¹⁰ is cycloalkyl or heterocycloalkyl;

R¹¹ is alkyl, each of which is unsubstituted or substituted with one ortwo or three of independently selected F, Cl, Br or I;

R¹⁷ is R²¹;

R²¹ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three independently selected F, Cl, Br or I;

Z¹ is R²⁶;

Z² is R³⁰;

Z^(1A) and Z^(2A) are both absent:

L¹ is a R³⁷;

R²⁶ is phenylene;

R³⁰ is heterocycloalkylene;

R³⁷ is R^(37A);

R^(37A) is alkylene, alkenylene, or alkynylene, each of which isunsubstituted or substituted with one or two or three independentlyselected F, Cl, Br or I substituents;

Z³ is R³⁸, or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with R^(38A)R^(38A) isheterocycloalkane;

R³⁸ is cycloalkenyl, or heterocycloalkenyl;

wherein the moieties represented by R²⁶ and R²⁷ are substituted (i.e.,if Z^(1A) and Z^(2A) are absent) or further substituted (i.e., if Z^(1A)and Z^(2A) are present) with one or two or three or four ofindependently selected R⁴¹, OR⁴¹, or NHR⁴¹;

R⁴¹ is R⁴², R⁴³, or R⁴⁵;

R⁴² is phenyl, which is unfused or fused with heteroarene or R^(42A);R^(42A) is heterocycloalkane;

R⁴³ is heteroaryl, which is unfused or fused with heteroarene;

R⁴⁵ is alkyl, each of which is unsubstituted or substituted with one ortwo or three of independently selected F, Cl, Br or I;

R⁴⁶ is R⁴⁷; or R⁴⁸;

R⁴⁷ is phenyl;

R⁴⁸ is heteroaryl;

wherein the moieties represented R⁴², R^(42A), R⁴³, R^(43A), R⁴⁴,R^(44A), R⁴⁷, R^(47A), R⁴⁸, R^(48A), R⁴⁹, R^(49A) are independentlysubstituted with one or two or three or four of independently selectedR⁵⁰, OR⁵⁰, CO(O)R⁵⁰, NH₂, NHR⁵⁰, N(RR⁵⁰)₂, NHC(O)R⁵⁰, NHS(O)₂R⁵⁰,NHC(O)OR⁵⁰, C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, OH, (O), CN, NO₂, CF₃, F,Cl, Br, or I;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl;

R⁵² is heteroaryl;

R⁵³ is cycloalkyl or heterocycloalkyl;

R⁵⁴ is alkyl, each of which is unsubstituted or substituted with one ortwo or three of independently selected R⁵⁵, OR⁵⁵, C(O)R⁵⁵, NH₂, NHR⁵⁵,N(R⁵⁵)₂, NR⁵⁵C(O)OR⁵⁵, C(O)N(R⁵⁵)₂, OH, F, Cl, Br or I;

R⁵⁵ is alkyl, phenyl, or heterocycloalkyl; and

wherein each foregoing cyclic moiety is independently unsubstituted,further unsubstituted, substituted or further substituted with one ortwo or three or four or five of independently selected R^(57A), R⁵⁷,OR⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷, C(O)R⁵⁷, NH₂, NHR⁵⁷, N(R⁵⁷)₂, OH, (O), CN, F, Cl,Br or I;

R^(57A) is spirocyclyl;

R⁵⁷ is R⁵⁸, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl;

R⁶⁰ is cycloalkyl, or heterocycloalkyl;

R⁶¹ is alkyl, or alkenyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R⁶², OR⁶², N(R⁶²)₂,C(O)N(R⁶²)₂, OH, F, Cl, Br or I;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl;

R⁶⁴ is heteroaryl;

R⁶⁵is cycloalkyl, or heterocycloalkyl;

R⁶⁶ is alkyl, each of which is unsubstituted or substituted with one ortwo or three of independently selected OR⁶⁷, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl;

wherein the moieties represented by R^(57A) , R⁵⁸, R⁵⁹, R⁶⁰, R⁶³, R⁶⁴,R⁶⁵, and R⁶⁷ are unsubstituted or substituted with one or two or threeor four of independently selected R⁶⁸F, Cl, Br or I;

R⁶⁸ is R⁷¹ or R⁷²;

R⁷¹ heterocycloalkyl; and

R⁷² is alkyl which is unsubstituted or substituted with one or two orthree of independently selected F, Cl, Br or I;

Still another embodiment pertains to compounds having Formula (I), whichare

-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylamino)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((2methyl-1H-indol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxymethyl)phenoxy-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((1-methyl-1H-indol-4-)yl)oxy)benzamide;-   2-(3-(acetylamino)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(4-aminophenoxy-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(3-aminophenoxy-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyphenyl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl))-2-(3-dimethylamino)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl))-2-(3-cyanophenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1,3-benzothiazol-6-yl)oxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl))-2-((2-methyl-1,3-benzothiazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-((2-methyl-1,3-benzothiazol-5-yl)oxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimethylamino)-3-oxopropyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimethylamino)-2-oxoethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-dimethylamino)propyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)-N,N-dimethylbenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-morpholin-4-ylphenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dimethyl-1,3-thiazol-5-yl)phenyoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(3,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)ethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-isopropylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indazol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-ethylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1,2,2,6,6-pentamethylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((7-fluoro-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-((4′-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indazol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(3-(trifluoromethyl)phenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2-chloro-3-(trifluoromethyl)phenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopropylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1H-indol-4-yl)oxy)    -N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-morpholin-4-ylphenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((3-(3-morpholin-4-yl-3-oxopropyl)-1H-indol-5-yl)oxy)benzamide;-   2-(2-benzylxoy)phenoxy)-4-(4-((4′-chloro)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pryan-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-cyanophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpholin-4-yl-3-oxopropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpholin-4-ylpropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-(1H-imidazol-1-yl)-phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophenoxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   tert-butyl    4-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)benzyl(ethyl)carbamate;-   tert-butyl    3-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)benzyl(ethyl)carbamate;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-((ethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((ethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(4-(acetylamino)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   tert-butyl    4-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenylcarbamate;-   2-(1,1′-biphenyl-2-yloxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   tert-butyl    3-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenylcarbamate;-   2-(1,1′-biphenyl-3-yloxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(4-(benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-morpholin-4-ylphenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1,3-benzothiazol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   tert-butyl    4-(3-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenyl)piperazine-1-carboxylate;-   2-(3-(benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-(benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morpholin-4-ylethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)benzamide;-   2-(4-benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   tert-butyl    4-(4-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)amino)carbonyl)phenoxy)phenyl)piperazine-1-caraboxylate;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-pyridin-4-ylphenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-4-ylphenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-3-ylphenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1H-benzimidazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-benzamide;-   4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylcarbamoyl)phenoxy)-N-(4-(3-morpholinopropylamino-3-nitrophenylsulfonyl)benzamide;-   4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propylamino)-3-nitrophenylsulfonyl)-2-(3-(methylcarbamoyl)phenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(dimethylamino)propyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-(hydroxymethyl)phenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-methoxybenzyl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrophenylsulfonyl-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide;-   4-(4-((4′-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide;-   N-{[4-{4-[(4′chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]-3-nitrobenzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(4-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-4-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2,3-difluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(3-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2,3-difluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(3-nitro-4-{[1-(thien-3-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(4-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-(2-fluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(1methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-({4-[(1-allylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)benzamide;-   2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide;-   2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(4-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[3-(methoxymethoxy)-2-methylphenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-hydroxy-2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-bromophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(3-iodophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2-phenylethyl)-piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3,4-dichlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-3,5-difluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[3-hydroxymethyl)phenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(2-methoxyethoxy)ethyl]piperidin-4-yl)}amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-3-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(3-phenylpropyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-ethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-hydroxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[6-(4-chlorophenyl)-1,3-benzodioxol-5-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(dimethylamino)-2-oxoethyl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-morpholin-4-ylethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[3-(1H-pyrrol-2-yl)phenoxy]benzamide;-   4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   tert-butyl    4-(5-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)amino]carbonyl}phenoxy)-1H-indole-1-carboxylate;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   Trans-2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(2-chlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   2-({1,3-bis[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-({3-[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)benzamide;-   2-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonylcarbamoyl)pheonxy)-N,N-dimethylbenzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-{[2-(trifluoromethyl)-1H-indol-4-yl]oxy}benzamide;-   2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   (4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-{[6-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-{[6-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide;-   2-[(2-amino-1,3-thiazol-4-yl)methoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   tert-butyl    4-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)amino]carbonyl}phenoxy)methyl]-1,3-thiazol-2-ylcarbamate;-   2-[(2-amino-1,3-thiazol-4-yl)methoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[3-(acetylamino)phenoxy]-(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[3-(acetylamino)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   2-[(2-chlorophenyl)amino]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-methoxy-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(2-chlorophenyl)amino]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   tert-butyl    5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]amino}carbonyl)phenoxy]-1H-indole-1-carboxylate;-   2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-[(6,7-difluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino-3-nitrophenyl]sulfonyl}benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-(4-amino-3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(3S,4R)-3-hydroxy-1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   2-(6-aminopyridin-3-yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   tert-butyl    5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate;-   2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyloxy)phenyl]sulfonyl}benzamide;-   2-[(3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   tert-butyl    5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;-   tert-butyl    4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;-   2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-[(5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   tert-butyl    5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-3-ylcarbamate;-   2-[5-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   tert-butyl    4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;-   2-[3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pryan-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-hydroxypyridin-3-yl)oxy]-N-({3-nitro-4-[(2-H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-{[6-(benzyloxy)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pryan-4ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro    2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[-(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   N-{[5-bromo-6-(1,4-dioxan-2ylmethoxy)pyridino-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-N-({5-bromo-6-[(4-morpholin-4ylcyclohexyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   2-(3-amino-5-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3-nitrophenyl}sulfonyl)benzamide;-   N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-yl)oxy]pyridin-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[1-(4-methoxybenzyl)-1H-1,2,3-benzotriazol-4-yl]oxy}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}benzamide;-   Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-amino-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)nicotinamide;-   2-[(6-amino-5-cyanopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   2-{[6-(acetylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-methylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-isopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-cyclopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}benzamide;-   tert-butyl    6bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenyoxy)pyridin-2-ylcarbamate;-   tert-butyl    -4-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)pyridine-2,6-diyldicarbamate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[6-(cyclopropylamino)pyridin-3-yl]oxy}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-[(4-{[(4-(methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-{[5-chloro-6-(methylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-fluoro-1-(fluoromethyl)ethyl]morpholin-2yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(2-amino-6-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(2,6-diaminopyridin-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-3yl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   tert-butyl    5-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-({6-[(2,2,2-trifluoro)amino]pyridin-3-yl}oxy)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({9-(4-chlorophenyl)-3-[2-fluoro-1-(fluoromethyl)ethyl]-3-azaspiro[5.5]undec-8-en-8-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-[(2-amino-5-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(2,2-difluoroethyl)-4fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[2-(1H-pyrazol-4-yl)phenoxy]benzamide;-   2-[2-(2-aminopyridin-3-yl)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-)[2-(1H-pyrazol-5-yl)phenoxy]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}suflonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

Still another embodiment pertains to2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;and therapeutically acceptable salts, prodrugs, salts of prodrugs andmetabolites thereof.

Still another embodiment pertains to[3-chloro-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)-2-iminopyridin-1(2H)-yl]methyldihydrogen phosphate; and therapeutically acceptable salts, andmetabolites thereof.

In another aspect, the present invention provides compounds of Formula(II)

and therapeutically acceptable salts, prodrugs, salts of prodrugs andmetabolites thereof, wherein A¹, B¹, D¹, E¹, Y¹, Z², L¹, and Z³ are asdescribed herein for Formula (I), n is 0, 1, 2, or 3; describing thenumber of additional substituents on R²⁶, and R¹⁰⁰ is as described forsubstituents on R²⁶, m is 1, 2, 3, 4, or 5; describing the number ofsubstituents on R⁴², and R¹⁰¹ is as described for substituents on R⁴².

In one embodiment of Formula (II), A¹ is N. In another embodiment ofFormula (II), A¹ is C(A²). In another embodiment of Formula (II), A¹ isC(A²); and A² is H.

In another embodiment of Formula (II), B¹ is OR¹, or NHR¹. In anotherembodiment of Formula (II), A¹ is C(A²); A² is H; and B¹ is NHR¹. Inanother embodiment of Formula (II), A¹ is C(A²); A² is H; and B¹ is OR¹.

In one embodiment of Formula (II), D¹ is H. In another embodiment ofFormula (II), A¹ is C(A²); A² is H; B¹ is NHR¹; and D¹ is H. In anotherembodiment of Formula (II), A¹ is C(A²); A² is H; B¹ is OR¹; and D¹ isH.

In one embodiment of Formula (II), E¹ is H. In another embodiment ofFormula (II), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; and E¹ is H. Inanother embodiment of Formula (I), A¹ is C(A²); A² is H; B¹ is OR¹; D¹is H; and E¹ is H.

In one embodiment of Formula (II), Y¹ is H, CN, NO₂, F, Cl, Br, CF₃, R¹⁷or SO₂R¹⁷. In another embodiment of Formula (II), Y¹ is NO₂. In anotherembodiment of Formula (II), Y¹is Cl. In another embodiment of Formula(II), Y¹ is SO₂R¹⁷; wherein R¹⁷ is as defined herein. In anotherembodiment of Formula (II), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl. Inanother embodiment of Formula (II), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl.In another embodiment of Formula (II), A¹ is C(A²); A² is H; B¹ is NHR¹;D¹ is H; E¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl oralkynyl. In another embodiment of Formula (II), A¹ is C(A²); A² is H; B¹is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂. In another embodiment ofFormula (II), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹is SO₂R¹⁷, wherein R¹⁷is alkyl substituted with three F. In anotherembodiment of Formula (II), A¹ is C(A²); A² is H; B¹ is OR¹; D¹ is H; E¹is H; and Y¹ is Cl.

In one embodiment of Formula (II), R¹ is R⁴ or R⁵. In one embodiment ofFormula (II), R¹ is R⁴. In one embodiment of Formula (II), R¹ is R⁵. Inone embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl, orheterocycloalkyl. In one embodiment of Formula (II), R¹ is R⁴; and R⁴ iscycloalkyl. In one embodiment of Formula (II), R¹ is R⁴; and R⁴ isheterocycloalkyl.

In one embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is substituted as defined herein. In another embodimentof Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is substituted with R⁵⁷, NHR⁵⁷, or N(R⁵⁷)₂. In another embodimentof Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is cyclohexyl; and wherein the cyclohexyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (II), R¹ is R⁴; R⁴is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and whereinthe cyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰; and R⁶⁰ isheterocycloalkyl. In another embodiment of Formula (II), R¹ is R⁴; R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl orpiperazinyl. In another embodiment of Formula (II), R¹ is R⁴; and R⁴ iscycloalkyl; wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂. Inanother embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexylring is substituted with N(R⁵⁷)₂. In another embodiment of Formula (II),R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring iscycloalkyl; and wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂,R⁵⁷; and R⁵⁷ is R⁶¹, and R⁶¹ is alkyl which is unsubstituted. In anotherembodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with N(R⁵⁷)₂, R⁵⁷ is R⁶⁰, and R⁶⁰ is cycloalkyl which isunsubstituted. In another embodiment of Formula (II), R¹ is R⁴; and R⁴is cycloalkyl; wherein the cycloalkyl ring is substituted with NHR⁵⁷. Inanother embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexylring is substituted with NHR⁵⁷ In another embodiment of Formula (II), R¹is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl;and wherein the cyclohexyl ring is substituted with NHR⁵⁷, R⁵⁷ is R⁶⁰,and R⁶⁰ is heterocycloalkyl which is unsubstituted.

In one embodiment of Formula (II), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (II), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is substituted as defined herein. Inanother embodiment of Formula (II), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is substituted withR⁵⁷. In another embodiment of Formula (II), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; and wherein theheterocycloalkyl ring is substituted with one or two or three or four orfive more R⁵⁷, SO₂R⁵⁷, or OH, and R⁵⁷ is R⁶⁰ or R⁶¹. In anotherembodiment of Formula (II), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl,morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl,morpholinyl, or piperizinyl; ring is substituted R⁵⁷; and R⁵⁷ is R⁶⁰orR⁶¹; R⁶⁰ is cycloalkyl or heterocycloalkyl; and R⁶¹ is alkyl. In anotherembodiment of Formula (II), R¹ is R⁴; R⁴ is heterocycloalkyl; whereinthe heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl; ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl oroxetanyl. In another embodiment of Formula (II), R¹ is R⁴; R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷;R⁵⁷ is R⁶⁰; R⁶⁰ is cycloalkyl wherein the cycloalkyl is cyclopropyl orcyclopentyl. In another embodiment of Formula (II), R¹ is R⁴; R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one ortwo or three or four or five R⁵⁷; R⁵⁷ is R⁶¹; and R⁶¹ is alkyl; and thealkyl is C₁-alkyl, C₂-alkyl, or C₃-alkyl. In another embodiment ofFormula (II), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl ring is substituted with one or two or three or four or fiveR⁵⁷; R⁵⁷ is R⁶¹; R⁶¹ is alkyl; and the alkyl is C₁-alkyl, C₂-alkyl, orC₃-alkyl; wherein the C₁-alkyl, C₂-alkyl, or C₃-alkyl are unsubstitutedor substituted.

In one embodiment of Formula (II), R¹ is R⁵; and R⁵ is alkyl which isunsubstituted or substituted. In one embodiment of Formula (II), R¹ isR⁵; and R⁵ is alkyl which is unsubstituted or substituted with R⁷, OR⁷,N(R⁷)₂, or OH.

In one embodiment a Formula (II), R⁷ is R¹⁰ or R¹¹ which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (II), R⁷ is R¹⁰ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (II), R⁷ is R¹¹ which isunsubstituted or substituted as defined herein.

In one embodunent ot Formula (II), R¹⁰ is cycloalkyl or heterocycloalkylwhich are unsubstituted or substituted as defined herein. In anotherembodiment of Formula (II), R¹⁰ is heterocycloalkyl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (II), R¹⁰ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,dioxanyl, piperidinyl, piperizinyl, or pyrrolidinyl, which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (II), R¹⁰ is tetrahydropyranyl, which is unsubstituted orsubstituted as defined herein. In another embodiment of Formula (II),R¹⁰ is morpholinyl, which is unsubstituted or substituted as definedherein. In another embodiment of Formula (II), R¹⁰ is cycloalkyl whichis unsubstituted or substituted as defined herein. In another embodimentof Formula (II), R¹⁰ is cyclohexyl which is unsubstituted or substitutedas defined herein.

In one embodiment of Formula (II), R¹¹ is alkyl which is unsubstituted.In another embodiment of Formula (II), R¹¹ is methyl, which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (II), R¹¹ is alkyl, which is substituted as defined herein. Inanother embodiment of Formula (II), R¹¹ is alkyl, which is substitutedwith OR¹², R¹² is R¹⁶, and R¹⁶ is alkyl.

Still another embodiment pertains to compounds having Formula (II),which are

-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylamino)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxymethyl)phenoxy-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-(acetylamino)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(4-aminophenoxy-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(3-aminophenoxy-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyphenyl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-dimethylamino)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-cyanophenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimethylamino)-3-oxopropyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimethylamino)-2-oxoethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-dimethylamino)propyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)-N,N-dimethylbenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-morpholin-4-ylphenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dimethyl-1,3-thiazol-5-yl)phenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(3,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)ethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-isopropylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-ethylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1,2,2,6,6-pentamethylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-((4′-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(3-(trifluoromethyl)phenoxy)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2-chloro-3-(trifluoromethyl)phenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopropylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-morpholin-4-ylphenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-benzylxoy)phenoxy)-4-(4-((4′-chloro)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pryan-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-cyanophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-(1H-imidazol-1-yl)-phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophenoxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   tert-butyl    4-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)benzyl(ethyl)carbamate;-   tert-butyl    3-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)benzyl(ethyl)carbamate;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-((ethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((ethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(4-(acetylamino)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   tert-butyl    4-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenylcarbamate;-   2-(1,1′-biphenyl-2-yloxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   tert-butyl    3-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenylcarbamate;-   2-(1,1′-biphenyl-3-yloxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(4-(benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-morpholin-4-ylphenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   tert-butyl    4-(3-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenyl)piperazine-1-carboxylate;-   2-(3-(benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   2-(3-(benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morpholin-4-ylethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(4-benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   tert-butyl    4-(4-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)amino)carbonyl)phenoxy)phenyl)piperazine-1-caraboxylate;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-pyridin-4-ylphenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-4-ylphenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-3-ylphenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylcarbamoyl)phenoxy)-N-(4-(3-morpholinopropylamino-3-nitrophenylsulfonyl)benzamide;-   4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propylamino)-3-nitrophenylsulfonyl)-2-(3-(methylcarbamoyl)phenoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-(hydroxymethyl)phenoxy)benzamide;-   N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrophenylsulfonyl-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide;-   4-(4-((4′-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide;-   N-{[4-{4-[(4′chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]-3-nitrobenzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(4-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-4-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2,3-difluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(3-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2,3-difluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(3-nitro-4-{[1-(thien-3-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(4-fluorophenoxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-(2-fluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(1methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-({4-[(1-allylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)benzamide;-   2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide;-   2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[3-(methoxymethoxy)-2-methylphenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-hydroxy-2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-bromophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(3-iodophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2-phenylethyl)-piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3,4-dichlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-3,5-difluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[3-hydroxymethyl)phenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(2-methoxyethoxy)ethyl]piperidin-4-yl}amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-3-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(3-phenylpropyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-ethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-hydroxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[6-(4-chlorophenyl)-1,3-benzodioxol-5-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(dimethylamino)-2-oxoethyl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-morpholin-4-ylethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[3-(1H-pyrrol-2-yl)phenoxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1,4-dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1,4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   Trans-2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(2-chlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   2-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonylcarbamoyl)pheonxy)-N,N-dimethylbenzamide;-   2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-[3-(acetylamino)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[3-(acetylamino)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(4-tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-(4-amino)-3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2-H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)    propyl]amino}phenyl)sulfonyl]benzamide;-   2-(3-amino-5-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[2-(1H-pyrazol-4-yl)phenoxy]benzamide;-   2-[2-(2-aminopyridin-3-yl)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2-H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)    benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[2-(1H-pyrazol-5-yl)phenoxy]benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

In another aspect, the present invention provides compounds of Formula(III)

and therapeutically acceptable salts, prodrugs, salts of prodrugs andmetabolites thereof, wherein A¹, B¹, D¹, E¹, Y¹, Z², L¹, and Z³ are asdescribed herein for Formula (I), n is 0, 1, 2, or 3; describing thenumber of additional substituents on R²⁶, and R¹⁰⁰ is as described forsubstituents on R²⁶, and at least one R¹⁰² is a substituent on R⁴² andR^(42A), and the remainder are H.

In one embodiment of Formula (III), A¹ is N. In another embodiment ofFormula (III), A¹ is C(A²). In another embodiment of Formula (III), A¹is C(A²); and A² is H.

In another embodiment of Formula (III), B¹ is OR¹, or NHR¹. In anotherembodiment of Formula (III), A¹ is C(A²); A² is H; and B¹ is NHR¹. Inanother embodiment of Formula (III), A¹ is C(A²); A² is H; and B¹ isOR¹.

In one embodiment of Formula (III), D¹ is H. In another embodiment ofFormula (III), A¹ is C(A²); A² is H; B¹ is NHR¹; and D¹ is H. In anotherembodiment of Formula (III), A¹ is C(A²); A² is H; B¹ is OR¹; and D¹ isH.

In one embodiment of Formula (III), E¹ is H. In another embodiment ofFormula (III), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; and E¹ is H.In another embodiment of Formula (I), A¹ is C(A²); A² is H; B¹ is OR¹;D¹ is H; and E¹ is H.

In one embodiment of Formula (III), Y¹ is H, CN, NO₂, F, Cl, Br, CF₃,R¹⁷ or SO₂R¹⁷. In another embodiment of Formula (III), Y¹ is NO₂. Inanother embodiment of Formula (III), Y¹is Cl. In another embodiment ofFormula (III), Y¹ is SO₂R¹⁷; wherein R¹⁷ is as defined herein. Inanother embodiment of Formula (III), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl.In another embodiment of Formula (III), Y¹ is R¹⁷; wherein R¹⁷ isalkynyl. In another embodiment of Formula (III), A¹ is C(A²); A² is H;B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ isalkyl or alkynyl. In another embodiment of Formula (II), A¹ is C(A²); A²is H; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂. In another embodimentof Formula (III), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H;and Y¹ is SO₂R¹⁷, wherein R¹⁷is alkyl substituted with three F. Inanother embodiment of Formula (III), A¹ is C(A²); A² is H; B¹ is OR¹; D¹is H; E¹ is H; and Y¹ is Cl.

In one embodiment of Formula (III), R¹ is R⁴ or R⁵. In one embodiment ofFormula (III), R¹ is R⁴. In one embodiment of Formula (III), R¹ is R⁵.In one embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl, orheterocycloalkyl. In one embodiment of Formula (III), R¹ is R⁴; and R⁴is cycloalkyl. In one embodiment of Formula (III), R¹ is R⁴; and R⁴ isheterocycloalkyl.

In one embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is substituted as defined herein. In another embodimentof Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is substituted with R⁵⁷, NHR⁵⁷, or N(R⁵⁷)₂. In another embodimentof Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is cyclohexyl; and wherein the cyclohexyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (III), R¹ is R⁴;R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and whereinthe cyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰; and R⁶⁰ isheterocycloalkyl. In another embodiment of Formula (III), R¹ is R⁴; R⁴is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and whereinthe cyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl orpiperazinyl. In another embodiment of Formula (III), R¹ is R⁴; and R⁴ iscycloalkyl; wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂. Inanother embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexylring is substituted with N(R⁵⁷)₂. In another embodiment of Formula(III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring iscyclohexyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)₂,R⁵⁷ is R⁶¹, and R⁶¹ is alkyl which is unsubstituted. In anotherembodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with N(R⁵⁷)₂, R⁵⁷ is R⁶⁰, and R⁶⁰ is cycloalkyl which isunsubstituted. In another embodiment of Formula (III), R¹ is R⁴; and R⁴is cycloalkyl; wherein the cycloalkyl ring is substituted with NHR⁵⁷. Inanother embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexylring is substituted with NHR⁵⁷. In another embodiment of Formula (III),R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring iscyclohexyl; and wherein the cyclohexyl ring is substituted with NHR⁵⁷,R⁵⁷ is R⁶⁰, and R⁶⁰ is heterocycloalkyl which is unsubstituted.

In one embodiment of Formula (III), R¹ is R⁴; and R⁴ isheteroeycioalkyl; wherein R⁴ is unsubstituted or substituted as definedherein. In another embodiment of Formula (III), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is substituted asdefined herein. In another embodiment of Formula (III), R¹ is R⁴; and R⁴is heterocycloalkyl; wherein the heterocycloalkyl ring is substitutedwith R⁵⁷. In another embodiment of Formula (III), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; and wherein theheterocycloalkyl ring is substituted with one or two or three or four orfive more R⁵⁷; SO₂R⁵⁷, or OH, and R⁵⁷ is R⁶⁰ or R⁶¹. In anotherembodiment of Formula (III), R¹ is R⁴; R⁴ is heterocycloalkyl; whereinthe heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl; ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰ or R⁶¹; R⁶⁰ iscycloalkyl or heterocycloalkyl; and R⁶¹ is alkyl. Inanother embodimentof Formula (III), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl; ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl oroxetanyl. In another embodiment of Formula (III), R¹ is R⁴; R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷;R⁵⁷ is R⁶⁰; R⁶⁰ cycloalkyl, wherein the cycloalkyl is cyclopropyl orcyclopentyl. In another embodiment of Formula (III), heterocycloalkyl;R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring ispiperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and wherein thepiperidinyl, pyrrolinyl, morpholinyl, or piperidinyl ring is substitutedwith one or two or three or four or five R⁵⁷; R⁵⁷ is R⁶¹, R⁶¹ is alkyl;and the alkyl is C₁-alkyl, C₂-alkyl, or C₃-alkyl. In another embodimentof Formula (II), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl ring is substituted with one or two or three or four or fiveR⁵⁷; R⁵⁷ is R⁶¹; R⁶¹ is alkyl; and the alkyl is C₁-alkyl, C₂-alkyl, orC₃-alkyl; wherein the C₁-alkyl, C₂-alkyl, or C₃-alkyl are unsubstitutedor substituted.

In one embodiment of Formula (III), R¹ is R⁵; and R⁵ is alkyl which isunsubstituted or substituted. In one embodiment of Formula (II), R¹ isR⁵; and R⁵ is alkyl which is unsubstituted or substituted with R⁷, OR⁷,N(R⁷)₂, or OH.

In one embodiment a Formula (III), R⁷ is R¹⁰ or R¹¹ which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (III), R⁷ is R¹⁰ which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (III), R⁷ is R¹¹ whichis unsubstituted or substituted as defined herein.

In one embodunent ot Formula (III), R¹⁰ is cycloalkyl orheterocycloalkyl which are unsubstituted or substituted as definedherein. In another embodiment of Formula (III), R¹⁰ is heterocycloalkylwhich is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (III), R¹⁰ is tetrahydrofuranyl,tetrahydropyranyl, morpholinyl, dioxanyl, piperidinyl, piperizinyl, orpyrrolidinyl, which are unsubstituted or substituted as defined herein.In another embodiment of Formula (III), R¹⁰ is tetrahydropyranyl, whichis unsubstituted or substituted as defined herein. In another embodimentof Formula (III), R¹⁰ is morpholinyl, which is unsubstituted orsubstituted as defined herein. In another embodiment of Formula (III),R¹⁰ is cycloalkyl which is unsubstituted or substituted as definedherein. In another embodiment of Formula (III), R¹⁰ is cyclohexyl whichis unsubstituted or substituted as defined herein.

In one embodiment of Formula (III), R¹¹ is alkyl which is unsubstituted.In another embodiment of Formula (III), R¹¹ is methyl, which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (III), R¹¹ is alkyl, which is substituted as defined herein. Inanother embodiment of Formula (III), R¹¹ is alkyl, which is substitutedwith OR¹², R¹² is R¹⁶, and R¹⁶ is alkyl.

Still another embodiment pertains to compounds having Formula (III),which are

-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((2methyl-1H-indol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((7-fluoro-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((3-(3-morpholin-4-yl-3-oxopropyl)-1H-indol-5-yl)oxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(morpholin-4-yl-3-oxopropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(morpholin-4-ylpropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(dimethylamino)propyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(4-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   (4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-{[6-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide;-   (4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-{[6-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-methoxy-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   tert-butyl    5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]amino}carbonyl)phenoxy]-1H-indole-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-[(6,7-difluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-({[4-(hyd    yl]methyl}amino-3-nitrophenyl]sulfonyl}benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(3S,4R)-3-hydroxy-1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyloxy)phenyl]sulfonyl}benzamide;-   2-[(3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}benzamide;-   2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro    2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[-(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   N-{[5-bromo-6-(1,4-dioxan-2ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-N-({5-bromo-6-[(4-morpholin-4ylcyclohexyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3-nitrophenyl}sulfonyl)benzamide;-   N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6fluoro-1H-indol-5-yl)oxy]benzamide;-   N-({5-chloro-6-[(4,4-difluorocyclohexyl-methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6fluoro-1H-indol-5-yl)oxy]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;    and therapeutically acceptable salts, prodrug, salts of prodrugs and    metabolites thereof.

In another aspect, the present invention provides compounds of Formula(IV)

and therapeutically acceptable salts, prodrugs, salts of prodrugs andmetabolites thereof, wherein A¹, B¹, D¹, E¹, Y¹, Z², L¹, and Z³ are asdescribed herein for Formula (I), n is 0, 1, 2, or 3; describing thenumber of additional substituents on R²⁶, and R¹⁰⁰ is as described forsubstituents on R²⁶, and at least one R¹⁰² is a substituent as describedfor substituents on R⁴² R^(42A), and the remainder are H.

In one embodiment of Formula (IV), A¹ is N. In another embodiment ofFormula (IV), A¹ is C(A²). In another embodiment of Formula (IV), A¹ isC(A²); and A² is H.

In one embodiment of Formula (IV), B¹ is OR¹, or NHR¹. In anotherembodiment of Formula (IV), A¹ is C(A²); A² is H; and B¹ is NHR¹. Inanother embodiment of Formula (IV), A¹ is C(A²); A² is H; and B¹ is OR¹.

In one embodiment of Formula (IV), D¹ is H. In another embodiment ofFormula (IV), A¹ is C(A²); A² is H; B¹ is NHR¹; and D¹ is H. In anotherembodiment of Formula (IV), A¹ is C(A²); A² is H; B¹ is OR¹; and D¹ isH.

In one embodiment of Formula (IV), E¹ is H. In another embodiment ofFormula (IV), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; and E¹ is H. Inanother embodiment of Formula (I), A¹ is C(A²); A² is H; B¹ is OR¹; D¹is H; and E¹ is H.

In one embodiment of Formula (IV), Y¹ is H, CN, NO₂, F, Cl, Br, CF₃, R¹⁷or SO₂R¹⁷. In another embodiment of Formula (IV), Y¹ is NO₂. In anotherembodiment of Formula (IV), Y¹is Cl. In another embodiment of Formula(IV), Y¹ is SO₂R¹⁷; wherein R¹⁷ is as defined herein. In anotherembodiment of Formula (IV), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl. Inanother embodiment of Formula (IV), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl.In another embodiment of Formula (IV), A¹ is C(A²); A² is H; B¹ is NHR¹;D¹ is H; E¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl oralkynyl. In another embodiment of Formula (IV), A¹ is C(A²); A² is H; B¹is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂. In another embodiment ofFormula (IV), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹is SO₂R¹⁷, wherein R¹⁷is alkyl substituted with three F. In anotherembodiment of Formula (IV), A¹ is C(A²); A² is H; B¹ is OR¹; D¹ is H; E¹is H; and Y¹ is Cl.

In one embodiment of Formula (IV), R¹ is R⁴ or R⁵. In one embodiment ofFormula (IV), R¹ is R⁴. In one embodiment of Formula (IV), R¹ is R⁵. Inone embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl, orheterocycloalkyl. In one embodiment of Formula (IV), R¹ is R⁴; and R⁴ iscycloalkyl. In one embodiment of Formula (IV), R¹ is R⁴; and R⁴ isheterocycloalkyl.

In one embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is substituted as defined herein. In another embodimentof Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is substituted with R⁵⁷, NHR⁵⁷, or N(R⁵⁷)₂. In another embodimentof Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is cyclohexyl; and wherein the cyclohexyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (IV), R¹ is R⁴; R⁴is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and whereinthe cyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰; and R⁶⁰ isheterocycloalkyl. In another embodiment of Formula (IV), R¹ is R⁴; R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl orpiperazinyl. In another embodiment of Formula (IV), R¹ is R⁴; and R⁴ iscycloalkyl; wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂. Inanother embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexylring is substituted with N(R⁵⁷)₂. In another embodiment of Formula (IV),R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring iscycloalkyl; and wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂,R⁵⁷; and R⁵⁷ is R⁶¹, and R⁶¹ is alkyl which is unsubstituted. In anotherembodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with N(R⁵⁷)₂, R⁵⁷ is R⁶⁰, and R⁶⁰ is cycloalkyl which isunsubstituted. In another embodiment of Formula (IV), R¹ is R⁴; and R⁴is cycloalkyl; wherein the cycloalkyl ring is substituted with NHR⁵⁷. Inanother embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexylring is substituted with NHR⁵⁷ In another embodiment of Formula (IV), R¹is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl;and wherein the cyclohexyl ring is substituted with NHR⁵⁷, R⁵⁷ is R⁶⁰,and R⁶⁰ is heterocycloalkyl which is unsubstituted.

In one embodiment of Formula (IV), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (IV), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is substituted as defined herein. Inanother embodiment of Formula (IV), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is substituted withR⁵⁷. In another embodiment of Formula (IV), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; and wherein theheterocycloalkyl ring is substituted with one or two or three or four orfive more R⁵⁷, SO₂R⁵⁷, or OH, and R⁵⁷ is R⁶⁰ or R⁶¹. In anotherembodiment of Formula (IV), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl,morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl,morpholinyl, or piperizinyl; ring is substituted R⁵⁷; and R⁵⁷ is R⁶⁰orR⁶¹; R⁶⁰ is cycloalkyl or heterocycloalkyl; and R⁶¹ is alkyl. In anotherembodiment of Formula (IV), R¹ is R⁴; R⁴ is heterocycloalkyl; whereinthe heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl; ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl oroxetanyl. In another embodiment of Formula (IV), R¹ is R⁴; R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷;R⁵⁷ is R⁶⁰; R⁶⁰ is cycloalkyl wherein the cycloalkyl is cyclopropyl orcyclopentyl. In another embodiment of Formula (II), R¹ is R⁴; R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one ortwo or three or four or five R⁵⁷; R⁵⁷ is R⁶¹; and R⁶¹ is alkyl; and thealkyl is C₁-alkyl, C₂-alkyl, or C₃-alkyl. In another embodiment ofFormula (IV), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl ring is substituted with one or two or three or four or fiveR⁵⁷; R⁵⁷ is R⁶¹; R⁶¹ is alkyl; and the alkyl is C₁-alkyl, C₂-alkyl, orC₃-alkyl; wherein the C₁-alkyl, C₂-alkyl, or C₃-alkyl are unsubstitutedor substituted.

In one embodiment of Formula (IV), R¹ is R⁵; and R⁵ is alkyl which isunsubstituted or substituted. In one embodiment of Formula (IV), R¹ isR⁵; and R⁵ is alkyl which is unsubstituted or substituted with R⁷, OR⁷,N(R⁷)₂, or OH.

In one embodiment a Formula (IV), R⁷ is R¹⁰ or R¹¹ which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (IV), R⁷ is R¹⁰ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (IV), R⁷ is R¹¹ which isunsubstituted or substituted as defined herein.

In one embodunent ot Formula (IV), R¹⁰ is cycloalkyl or heterocycloalkylwhich are unsubstituted or substituted as defined herein. In anotherembodiment of Formula (IV), R¹⁰ is heterocycloalkyl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (IV), R¹⁰ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,dioxanyl, piperidinyl, piperizinyl, or pyrrolidinyl, which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (IV), R¹⁰ is tetrahydropyranyl, which is unsubstituted orsubstituted as defined herein. In another embodiment of Formula (IV),R¹⁰ is morpholinyl, which is unsubstituted or substituted as definedherein. In another embodiment of Formula (IV), R¹⁰ is cycloalkyl whichis unsubstituted or substituted as defined herein. In another embodimentof Formula (IV), R¹⁰ is cyclohexyl which is unsubstituted or substitutedas defined herein.

In one embodiment of Formula (IV), R¹¹ is alkyl which is unsubstituted.In another embodiment of Formula (IV), R¹¹ is methyl, which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (IV), R¹¹ is alkyl, which is substituted as defined herein. Inanother embodiment of Formula (IV), R¹¹ is alkyl, which is substitutedwith OR¹², R¹² is R¹⁶, and R¹⁶ is alkyl.

Still another embodiment pertains to compounds having Formula (IV),which are

-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((1-methyl-1H-indol-4-yl)oxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3methyl-1H-indol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   tert-butyl    4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)amino]carbonyl}phenoxy)-1H-indole-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;-   2-({1,3-bis[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-({3-[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-{[2-(trifluoromethyl)-1H-indol-4-yl]oxy}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

In another aspect, the present invention provides compounds of Formula(V)

and therapeutically acceptable salts, prodrugs, salts of prodrugs andmetabolites thereof, wherein A¹, B¹, D¹, E¹, Y¹, Z², L¹, and Z³ are asdescribed herein for Formula (I), n is 0, 1, 2, or 3; describing thenumber of additional substituents on R²⁶, and R¹⁰⁰ is as described forsubstituents on R²⁶, and at least one of R¹⁰³ or R¹⁰⁴ is a substituentas described for substituents on R⁴² and R^(42A) , and the remainder areH.

In one embodiment of Formula (V), R¹⁰⁴ is NH₂. In another embodiment ofFormula (V), R¹⁰⁴ is NH₂.

In another embodiment of Formula (V), A¹ is N. In another embodiment ofFormula (V), A¹ is C(A²). In another embodiment of Formula (V), A¹ isC(A²); and A² is H.

In one embodiment of Formula (V), B¹ is OR¹, or NHR¹. In anotherembodiment of Formula (V), A¹ is C(A²); A² is H; B¹ is NHR¹. In anotherembodiment of Formula (V), A¹ is C(A²); A² is H; and B¹ is OR¹.

In one embodiment of Formula (V), D¹ is H. In another embodiment ofFormula (V), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H. In anotherembodiment of Formula (V), A¹ is C(A²); A² is H; B¹ is OR¹; D¹ is H.

In one embodiment of Formula (V), E¹ is H. In another embodiment ofFormula (V), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; and E¹ is H. Inanother embodiment of Formula (I), A¹ is C(A²); A² is H; B¹ is OR¹; D¹is H; and E¹ is H.

In one embodiment of Formula (V), Y¹is H, CN, NO₂, F, Cl, Br, CF₃, R¹⁷,or SO₂R¹⁷. In another embodiment of Formula (V), Y¹ is NO₂. In anotherembodiment of Formula (V), Y¹ is Cl. In another embodiment of Formula(V), Y¹ is SO₂R¹⁷; wherein R¹⁷ is as defined herein. In anotherembodiment of Formula (V), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl. Inanother embodiment of Formula (V), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl. Inanother embodiment of Formula (V), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹is H; E¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl or alkynyl.In another embodiment of Formula (V), A¹ is C(A²); A² is H; B¹ is NHR¹;D¹ is H; E¹ is H; and Y¹ is NO₂. In another embodiment of Formula (V),A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹ is SO₂R¹⁷,wherein R¹⁷ is alkyl substituted with three F. In another embodiment ofFormula (V), A¹ is C(A²); A² is H; B¹ is OR¹; D¹ is H; E¹ is H; and Y¹is Cl.

In one embodiment of Formula (V), R¹ is R⁴ or R⁵. In one embodiment ofFormula (V), R¹ is R⁴. In one embodiment of Formula (V), R¹ is R⁵. Inone embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl, orheterocycloalkyl. In one embodiment of Formula (V), R¹ is R⁴; and R⁴ iscycloalkyl. In one embodiment of Formula (V), R¹ is R⁴; and R⁴ isheterocycloalkyl.

In one embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is substituted as defined herein. In another embodimentof Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is substituted with R⁵⁷, NHR⁵⁷, or N(R⁵⁷)₂. In another embodimentof Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is cyclohexyl; and wherein the cyclohexyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (V), R¹ is R⁴; R⁴is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and whereinthe cyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰; and R⁶⁰ isheterocycloalkyl. In another embodiment of Formula (V), R¹ is R⁴; R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl orpiperazinyl. In another embodiment of Formula (V), R¹ is R⁴; and R⁴ iscycloalkyl; wherein the cyeloalkyl ring is substituted with N(R⁵⁷)₂. Inanother embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexylring is substituted with N(R⁵⁷)₂. In another embodiment of Formula (V),R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring iscycloalkyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)₂,R⁵⁷ is R⁶¹, and R⁶¹ is alkyl which is unsubstituted. In anotherembodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with N(R⁵⁷)₂, R⁵⁷ is R⁶⁰, and R⁶⁰ is cycloalkyl which isansubstituted. In another embodiment of Formula (V), R¹ is R⁴; and R⁴ iscycloalkyl; wherein the cycloalkyl ring is substituted with NHR⁵⁷. Inanother embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexylring is substituted with NHR⁵⁷. In another embodiment of Formula (V), R¹is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl;and wherein the cyclohexyl ring is substituted with N(R⁵⁷)₂, R⁵⁷ is R⁶⁰,and R⁶⁰ is heterocycloalkyl which is unsubstituted.

In one embodiment of Formula (V), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (V), R¹ is R⁴; and R⁴ is heterocycloalkyl; whereinthe heterocycloalkyl ring is substituted as defined herein. In anotherembodiment of Formula (V), R¹ is R⁴; and R⁴ is heterocycloalkyl; whereinthe heterocycloalkyl ring is substituted with R⁵⁷. In another embodimentof Formula (V), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl; and wherein the heterocycloalkyl ring is substituted withone or two or three or four or five more R⁵⁷, SO₂R⁵⁷, or OH, and R⁵⁷ isR⁶⁰ or R⁶¹. In another embodiment of Formula (V), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted R⁵⁷; R⁵⁷ isR⁶⁰or R⁶¹; R⁶⁰ is cycloalkyl or heterocycloalkyl; and R⁶¹ is alkyl. Inanother embodiment of Formula (V), R¹ is R⁴; R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl,morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl,morpholinyl, or piperizinyl; ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰;R⁶⁰ is heterocycloalkyl, wherein the heterocycloalkyl istetrahydropyranyl or oxetanyl. In another embodiment of Formula (V), R¹is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring ispiperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein thepiperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring issubstituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ is cycloalkyl, wherein thecycloalkyl is cyclopropyl or cyclopentyl. In another embodiment ofFormula (V), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl ring is substituted with one or two or three or four or fiveR⁵⁷; R⁵⁷ is R⁶¹; R⁶¹ is alkyl; and the alkyl is C₁-alkyl, C₂-alkyl, orC₃-alkyl. In another embodiment of Formula (V), R¹ is R⁴; R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl or piperizinyl, and wherein the piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one ortwo or three or four or five R⁵⁷; R⁵⁷ is R⁶¹; R⁶¹ is alkyl; and thealkyl is C₁-alkyl, C₂-alkyl, or C₃-alkyl; wherein the C₁-alkyl,C₂-alkyl, or C₃-alkyl are unsubstituted or substituted.

In one embodiment of Formula (V), R¹ is R⁵; and R⁵ is alkyl which isunsubstituted or substituted. In one embodiment of Formula (V), R¹ isR⁵; and R⁵ is alkyl which is unsubstituted or substituted with R⁷, OR⁷,N(R⁷)₂, or OH.

In one embodiment a Formula (V), R⁷ is R¹⁰ or R¹¹ which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (V), R⁷ is R¹⁰ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (V), R⁷ is R¹¹ which isunsubstituted or substituted as defined herein.

In one embodunent ot Formula (V), R¹⁰ is cycloalkyl or heterocycloalkylwhich are unsubstituted or substituted as defined herein. In anotherembodiment of Formula (V), R¹⁰ is heterocycloalkyl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (V), R¹⁰ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,dioxanyl, piperidinyl, piperizinyl, or pyrrolidinyl, which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (V), R¹⁰ is tetrahydropyranyl, which is unsubstituted orsubstituted as defined herein. In another embootment at Formula (V), R¹⁰is morpholinyl, which is unsubstituted or substituted as defined herein.In another embodiment of Formula (V), R¹⁰ is cycloalkyl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (V), R¹⁰ is cyclohexyl which is unsubstituted or substituted asdefined herein.

In one embodiment of Formula (V), R¹¹ is aikyl which is unsubstituted.In another embodiment of Formula (V), R¹¹ is methyl, which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (V), R¹¹ is alkyl, which is substituted as defined herein. Inanother embodiment of Formula (V), R¹¹ is alkyl, which is substitutedwith OR¹², R¹² is R¹⁶, and R¹⁶ is alkyl.

Still another embodiment pertains to compounds having Formula (V), whichare

-   2-(6-aminopyridin-3-yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   tert-butyl    5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;-   tert-butyl    4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-piperidin-4-yl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;-   2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-[(5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   tert-butyl    5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-3-ylcarbamate;-   2-[(5-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   tert-butyl    4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;-   2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-hydroxpyridin-3-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-{[6-(benzyloxy)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pryan-4ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-fluoropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}benzamide;-   Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4methoxycyclohexyl)methyl    ]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)nicotinamide;-   2-amino-[(6-amino-5-cyanopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   2-{[6-(acetylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(6-amino-5-methylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-isopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-cyclopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}benzamide;-   tert-butyl    6bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenyoxy)pyridin-2-ylcarbamate;-   tert-butyl    -4-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)pyridine-2,6-diyldicarbamate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[6-(cyclopropylamino)pyridin-3-yl]oxy}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-[(4-{[(4-(methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-{[5-chloro-6-(methylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-fluoro-1-(fluoromethyl)ethyl]morpholin-2yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-[(2-amino-6-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(2,6-diaminopyridin-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-3yl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   tert-butyl    5-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-({6-[(2,2,2-trifluoro)amino]pyridin-3-yl}oxy)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({9-(4-chlorophenyl)-3-[2-fluoro-1-(fluoromethyl)ethyl]-3-azaspiro[5.5]undec-8-en-8-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-[(2-amino-5-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluolro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[(6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamide;-   2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

In another aspect, the present invention provides compounds of Formula(VI)

and therapeutically acceptable salts, prodrugs, salts of prodrugs andmetabolites thereof, wherein A¹, B¹, D¹, E¹, Y¹, Z², L¹, and Z³ are asdescribed herein for Formula (I), n is 0, 1, 2, or 3; describing thenumber of additional substituents on R²⁶, and R¹⁰⁰ is as described forsubstituents on R²⁶, and at least one R¹⁰² is a substituent as describedfor substituents on R⁴² and R^(42A) , and the remainder are H.

In another embodiment of Formula (VI), A¹ is N. In another embodiment ofFormula (VI), A¹ is C(A²). In another embodiment of Formula (VI), A¹ isC(A²); and A² is H.

In one embodiment of Formula (VI), B¹ is OR¹, or NHR¹. In anotherembodiment of Formula (VI), A¹ is C(A²); A² is H; B¹ is NHR¹. In anotherembodiment of Formula (VI), A¹ is C(A²); A² is H; and B¹ is OR¹.

In one embodiment of Formula (VI), D¹ is H. In another embodiment ofFormula (VI), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H. In anotherembodiment of Formula (VI), A¹ is C(A²); A² is H; B¹ is OR¹; D¹ is H.

In one embodiment of Formula (VI), E¹ is H. In another embodiment ofFormula (VI), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; and E¹ is H. Inanother embodiment of Formula (I), A¹ is C(A²); A² is H; B¹ is OR¹; D¹is H; and E¹ is H.

In one embodiment of Formula (VI), Y¹is H, CN, NO₂, F, Cl, Br, CF₃, R¹⁷,or SO₂R¹⁷. In another embodiment of Formula (VI), Y¹ is NO₂. In anotherembodiment of Formula (VI), Y¹ is Cl. In another embodiment of Formula(VI), Y¹ is SO₂R¹⁷; wherein R¹⁷ is as defined herein. In anotherembodiment of Formula (VI), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl. Inanother embodiment of Formula (VI), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl.In another embodiment of Formula (VI), A¹ is C(A²); A² is H; B¹ is NHR¹;D¹ is H; E¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl oralkynyl. In another embodiment of Formula (VI), A¹ is C(A²); A² is H; B¹is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂. In another embodiment ofFormula (VI), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹is SO₂R¹⁷, wherein R¹⁷is alkyl substituted with three F. In anotherembodiment of Formula (VI), A¹ is C(A²); A² is H; B¹ is OR¹; D¹ is H; E¹is H; and Y¹ is Cl.

In one embodiment of Formula (VI), R¹ is R⁴ or R⁵. In one embodiment ofFormula (VI), R¹ is R⁴. In one embodiment of Formula (VI), R¹ is R⁵. Inone embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl, orheterocycloalkyl. In one embodiment of Formula (VI), R¹ is R⁴; and R⁴ iscycloalkyl. In one embodiment of Formula (VI), R¹ is R⁴; and R⁴ isheterocycloalkyl.

In one embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is substituted as defined herein. In another embodimentof Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is substituted with R⁵⁷, NHR⁵⁷, or N(R⁵⁷)₂. In another embodimentof Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is cyclohexyl; and wherein the cyclohexyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (VI), R¹ is R⁴; R⁴is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and whereinthe cyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰; and R⁶⁰ isheterocycloalkyl. In another embodiment of Formula (VI), R¹ is R⁴; R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl orpiperazinyl. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴ iscycloalkyl; wherein the cyeloalkyl ring is substituted with N(R⁵⁷)₂. Inanother embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexylring is substituted with N(R⁵⁷)₂. In another embodiment of Formula (VI),R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring iscycloalkyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)₂,R⁵⁷ is R⁶¹, and R⁶¹ is alkyl which is unsubstituted. In anotherembodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with N(R⁵⁷)₂, R⁵⁷ is R⁶⁰, and R⁶⁰ is cycloalkyl which isunsubstituted. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴is cycloalkyl; wherein the cycloalkyl ring is substituted with NHR⁵⁷. Inanother embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is cyclohexyl; and wherein the cyclohexylring is substituted with NHR⁵⁷. In another embodiment of Formula (VI),R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring iscyclohexyl; and wherein the cyclohexyl ring is substituted with N(R⁵⁷)₂,R⁵⁷ is R⁶⁰, and R⁶⁰ is heterocycloalkyl which is unsubstituted.

In one embodiment of Formula (VI), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (VI), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is substituted as defined herein. Inanother embodiment of Formula (VI), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is substituted withR⁵⁷. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; and wherein theheterocycloalkyl ring is substituted with one or two or three or four orfive more R⁵⁷, SO₂R⁵⁷, or OH, and R⁵⁷ is R⁶⁰ or R⁶¹. In anotherembodiment of Formula (VI), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is piperidinyl, pyrrolinyl,morpholinyl, or piperizinyl; and wherein the piperidinyl, pyrrolinyl,morpholinyl, or piperizinyl; ring is substituted R⁵⁷; R⁵⁷ is R⁶⁰or R⁶¹;R⁶⁰ is cycloalkyl or heterocycloalkyl; and R⁶¹ is alkyl. In anotherembodiment of Formula (VI), R¹ is R⁴; R⁴ is heterocycloalkyl; whereinthe heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl; and wherein the piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl; ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl oroxetanyl. In another embodiment of Formula (VI), R¹ is R⁴; R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; and wherein the piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl; ring is substituted with R⁵⁷;R⁵⁷ is R⁶⁰; R⁶⁰ is cycloalkyl, wherein the cycloalkyl is cyclopropyl orcyclopentyl. In another embodiment of Formula (VI), R¹ is R⁴; R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl, and wherein the piperidinyl,pyrrolinyl, morpholinyl, or piperizinyl ring is substituted with one ortwo or three or four or five R⁵⁷; R⁵⁷ is R⁶¹; R⁶¹ is alkyl; and thealkyl is C₁-alkyl, C₂-alkyl, or C₃-alkyl. In another embodiment ofFormula (VI), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl orpiperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl, orpiperizinyl ring is substituted with one or two or three or four or fiveR⁵⁷; R⁵⁷ is R⁶¹; R⁶¹ is alkyl; and the alkyl is C₁-alkyl, C₂-alkyl, orC₃-alkyl; wherein the C₁-alkyl, C₂-alkyl, or C₃-alkyl are unsubstitutedor substituted.

In one embodiment of Formula (VI), R¹ is R⁵; and R⁵ is alkyl which isunsubstituted or substituted. In one embodiment of Formula (VI), R¹ isR⁵; and R⁵ is alkyl which is unsubstituted or substituted with R⁷, OR⁷,N(R⁷)₂, or OH.

In one embodiment a Formula (VI), R⁷ is R¹⁰ or R¹¹ which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (VI), R⁷ is R¹⁰ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (VI), R⁷ is R¹¹ which isunsubstituted or substituted as defined herein.

In one embodunent ot Formula (VI), R¹⁰ is cycloalkyl or heterocycloalkylwhich are unsubstituted or substituted as defined herein. In anotherembodiment of Formula (VI), R¹⁰ is heterocycloalkyl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (VI), R¹⁰ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,dioxanyl, piperidinyl, piperizinyl, or pyrrolidinyl, which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (VI), R¹⁰ is tetrahydropyranyl, which is unsubstituted orsubstituted as defined herein. In another embootment at Formula (VI),R¹⁰ is morpholinyl, which is unsubstituted or substituted as definedherein. In another embodiment of Formula (VI), R¹⁰ is cycloalkyl whichis unsubstituted or substituted as defined herein. In another embodimentof Formula (VI), R¹⁰ is cyclohexyl which is unsubstituted or substitutedas defined herein.

In one embodiment of Formula (VI), R¹¹ is alkyl which is unsubstituted.In another embodiment of Formula (VI), R¹¹ is methyl, which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (VI), R¹¹ is alkyl, which is substituted as defined herein. Inanother embodiment of Formula (VI), R¹¹ is alkyl, which is substitutedwith OR¹², R¹² is R¹⁶, and R¹⁶ is alkyl.

Still another embodiment pertains to compounds having Formula (VI),which are4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide.

and therapeutically acceptable salts, prodrugs, salts of prodrugs andmetabolites thereof.

Pharmaceutical Compositions, Combination Therapies, Methods ofTreatment, and Administration

Another embodiment comprises pharmaceutical compositions comprising acompound having Formula (I) and an excipient.

Still another embodiment comprises methods of treating cancer in amammal comprising administering thereto a therapeutically acceptableamount of a compound having Formula (I).

Still another embodiment comprises methods of treating autoimmunedisease in a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseasesduring which antiapoptotic Bcl-2 proteins are expressed, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (I).

Still another embodiment pertains to methods of treating disease in apatient during which antiapoptotic Bcl-2 proteins are expressed, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, prostate cancer, small cell lung cancer or spleencancer, said compositions comprising an excipient and a therapeuticallyeffective amount of the compound having Formula (I).

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, prostate cancer, small cell lung cancer or spleen cancer in apatient, said methods comprising administering to the patient atherapeutically effective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseasesduring which are expressed anti-apoptotic Bcl-2 proteins, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (I) and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to methods of treating disease in apatient during which are expressed anti-apoptotic Bcl-2 proteins, saidmethods comprising administering to the patient a therapeuticallyefftctive amount of a compound having Formula (I) and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, brent cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer, said compositions comprising anexcipient and a therapeutically effective amount of the compound havingFormula (I) and a therapeutically effective amount of one additionaltherapeutic agent or more than one additional therapeutic agent.

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lyruphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, nonsmall cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said methods comprisingadministering to the patient a therapeutically effective amount of thecompound having Formula (I) and a therapeutically effective amount ofone additional therapeutic agent or more than one additional therapeuticagent.

Metabolites of compounds having Formula (I), produced by in vitro or invivo metabolic processes, may also have utility for treating diseasesassociated with anti-apoptotic Bcl-2 proteins.

Certain precursor compounds which may be metabolized in vitro or in vivoto form compounds having Formula (I) may also have utility for treatingdiseases associated with expression of anti-apoptotic Bcl-2 proteins.

Compounds having Formula (I) may exist as acid addition salts, basicaddition salts or zwitterions. Salts of the compounds are preparedduring isolation or following purification of the compounds. Acidaddition salts of the compounds are those derived from the reaction ofthe compounds with an acid. For example, the acetate, adipate, alginate,bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsufonate, digluconate, formate, fumarate,glyccrophosphate, glutamate, hemisulfate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate,maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate,propionate, succinate, tartrate, thiocyannate, trichloroacetic,trifluoroacetic, para-toluenesulfonate, and undecanoate salts of thecompounds and prodrugs thereof are contemplated as being embraced bythis invention. Basic addition salts of the compounds are those derivedfrom the reaction of the compounds with the hydroxide, carbonate orbicarbonate of cations such as lithium, sodium, potassium, calcium, andmagnesium.

The compounds having Formula (I) may be administered, for example,bucally, ophthalmically, orally, osmotically, parenterally(intramuscularly, intraperitoneally intrasternally, intravenously,subcutaneously), rectally, topically, transdermally or vaginally.

Therapeutically effective amounts of compounds having Formula (I) dependon the recipient of the treatment, the disorder being treated and theseverity thereof, the composition containing the compound, the time ofadministration, the route of administration, the duration of treatment,the compound potcncy, its rate of clearance and whether or not anotherdrug is co-administered. The amount of a compound of this inventionhaving Formula (I) used to make a composition to be administered dailyto a patient in a single dose or in divided doses is from about 0.03 toabout 200 mg/kg body weight. Single dose compositions contain theseamounts or a combination of submultiples thereof.

Compounds having Formula (I) may be administered with or without anexcipient. Excipients include, for example, encapsulating materials oradditives such as absorption accelerators, antioxidants, binders,buffers, coating agents, coloring agents, diluents, disintegratingagents, emulsifiers, extenders, fillers, flavoring agents, humectants,lubricants, perfumes, preservatIves, propellants, releasing agents,sterilizing agents, sweeteners, solubilizers, wetting agents andmixtures thereof.

Excipients for preparation of compositions comprising a compound havingFormula (I) to be administered orally in solid dosage form include, forexample, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzylbenzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose,cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil,cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate,ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonicsaline, lactose, magnesium hydroxide, magnesium stearate, malt,mannitol, monoglycerides, olive oil, peanut oil, potassium phosphatesalts, potato starch, povidone, propylene glycol, Ringer's solution,safflower oil, sesame oil, sodium carboxymethyl cellulose, sodiumphosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil,stearic acids, steayl fumarate, sucrose, surfactants, talc, tragacanth,tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered ophthalmically or orallyin liquid dosage forms include, for example, 1,3-butylene glycol, castoroil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan,germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethyleneglycols, propylene glycol, sesame oil, water and mixtures thereof.Exciepients for preparation of compositions comprising a compound ofthis invention having Formula (I) to be administered osmoticallyinclude, for example, chlorofluorohydrocarbons, ethanol, water andmixtures thereof. Excipients for preparation of compositions comprisinga compound of this invention having Formula (I) to be administeredparenterally include, for example, 1,3-butanediol, castor oil, corn oil,cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleicacid, olive oil, peanut oil, Ringer's solution, safflower oil, sesameoil, soybean oil, U.S.P. or isotonic sodium chloride solution, water andmixtures thereof. Excipients for preparation of compositions comprisinga compoand of this invention having Formula (I) to be administeredrectally or vaginally include, for example, cocoa butter, polyethyleneglycol, wax and mixtures thereof.

Compounds having Formula (I) are expected to be useful when used withalkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors,other apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-l)inhibitors, activators of death receptor pathway, Bcr-Abl kinaseininbitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drugconjugates, biologic response modifiers, cyclin-dependent kinaseinhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs,leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growthfactor inhibitors, heat shock protein (HSP)-90 inhibitors, histonedeacetylase (HDAC) inhibitors, hormonal therapies, immunologicals,inhibitors of inhibitors of apoptosis proteins (IAPs), intercalatingantibiotics, kinase inhibitors, microRNA's, mitogen-activatedextracellular signal-regulated kinase inhibitors, multivalent bindingproteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP(adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinumchemotherapeutics, polo-like knoase (Plk) inhibitors, phosphoinositide-3kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs,pyrimidine analogs, receptor tyrosine kinase inhibirors, etinoidsdeltodis, plant alkaloids, small inhibitory ribonucleic acids (siRNAs),topoisomerase inhibitors, ubiqutin ligase inhibitors, and the like, andin combination with one or more of these agents. BiTE antibodies arebi-specific antibodies that direct T-cells to attack cancer cells bysimultaneously binding the two cells. The T-cells then attacks thetarget cancer cell. Examples of BiTE antibodies include adecatumumab(Micromet MT201), blinatumomab (Micromet MT103) and the like. Withoutbeing limited by theory, one of the mechanisms by which T-cells elicitapoptosis of the target cancer cell is by exocytosis of cytolyticgranule components, which include perforin and granzyme B. in thisregard, Bcl-2 has been shown to attenuate the induction of apoptosis byboth perforin and granzyme B. These data suggest that inhibition ofBcl-2 could enhance the cytotoxic effects elicited by T-cells whentargeted to cancer cells (V. R. Sutton, D. L. Vaux and J. A. Trapani, J.of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2-deoxynucleotide, 2′-OCH3-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g, 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, us well as present on the 5′ and/or the3′-ends of a given strand. For example, siRNAs targeting MCl-1 have beenshown to enhance the activity of ABT-263, (i.e.,N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide)or ABT-737 (i.e.,N-(4-(4-(((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)in multiple tumor cell lines (Tse et. al, Cancer Research 2008, 68(9),3421 and references therein).

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site. Multispecific DVDs include DVD bindingproteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZTINE® (laromustine, VNP 40101M),lcyclophossphamide, decarbazine, estramustine, foternustine,glufosfamide, ifosfamide, KW-2170, lormustine (CCNU), mafosfamide,melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustardN-oxide, ranimustine, termozolormide, thiotepa, TREANDA® (bendamustine),treosulfan, rofosfamide and the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inbibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Anitmetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine)l armofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-riboruranosylimidazole-4-carboxamide), enocitabine,ethnylcytidien, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Auroroa B-specific kinaseinhibitors and pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((-)gossypol), GENASENSE® (G3139or oblimersen (Bcl-2 targeting antisense oligonucieotide)), IPI-194,IPI-565,N(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl0benzenesulfonamide(ABT-263), GX-070 (obatoclax) and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flabopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202), R-roscovitine) ZK-304709 and the like.

COX2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2O16,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine,EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA®(gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusionprotein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafamib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2ncu bispecificantibody, B7.her2IgG3, AS HER2 trifunctional bispecific antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-10I, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD-22-MCC-DM1, CR-011-veMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35,SGN-75 and the like.

Activators of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death neeptors (e.g., DR4 and DR5) such usApomab, conatumumab. ETR1-ST01, GDC0145, (lexatumumab), HGS-1029,LBY-135. PRO-1762 and trastuzumab.

Kinesin inhibitors include EG5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include; ARRY-142886, ARRY-438162 PD-325901, PD-914059and the like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal antiinflammatory drugs include AMIGESIC (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone). FELDENE® (piroxicam), ibuprofin cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(etodolac), TORADOL® (ketorolac), DAYPRO (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-838596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, EPT-45658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474), and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorabicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitracin,epirbucin, glarbuicin, ZAVEDOS® (idarnbicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocaraptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGFIR-specsfic antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD²⁰antibodies types I and II, GA101, ofatumumab, ABT-806 (mAb-806), ErbB3specific antibodies, BSG2 specific antibodies, DLL4 specific antibodiesand C-met specific antibodies, and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degareix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™(fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelasmer carbonate), lasofoxifene, leuprolide acetate,MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), ribostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant). VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and reinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin, ATGRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, incristine,vinglastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052,PR-171, and the like.

Examples of immunologicals include interfeons and other immune-enhancingagents. Interferons include interferon alpha, interferon alpha-2a,interferon alpha-2b, interferon beta, interferon gamm-1a, ACTIMMUNE®(interferon gamma-1b) or interferon gamma-n1, combinations thereof andthe like. Other agents include ALFAFERONE® , INF-α), BAM-002 (oxidizedglutathione), BEROMUN® (tasonermin), BEXXAR® (tositumomab), CAMPATH®(alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine,deniluekin, epratuzumab, GRANOCYTE® (lenograstim), lentinan, leukocytealpha interferon, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine,miturnomab, molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN®(filgrastim), Onco VAC-CL, OVAREX® (oregovomab), pemtumomab (Y-muHMFG1),PROVENGE® (sipulcucci-T), sargaramostim, sizofilan, teceleukin,THERACYS® (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN®(immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific Substance ofMaruyama (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)), PROLEUKIN®(aldesleukin), ZADAXIN® (thymalfasin), ZENAPAX® (daclizumab), ZAVALIN®(90Y-ibritumomab tiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofiran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiqutin ligase inhibitors include MDM2 inhibitor, such as nutlins,NEDD⁸ inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers thatenhance the efficacy of radiotherapy. Examples of radiotherapy includeexternal beam radiotherapy, teletherapy, brachytherapy and sealed,unsealed source radiotherapy and the like.

Additionally, compounds having Formula (I) may be combined wit otherchemotherapeutic agents such as ABRAXANE® (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA),APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin,L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene),AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papilloma virus vaccine),CHOP® (C:CYTOXAN® (cyclophosphamide; H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™(cyproterone acetate), combrestatin A⁴P, DAB (389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycm, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), cazastaurin,EPO906 (epithilone B), GARDASIL® (quadrivalent human papilloma virus(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®,GMK (ganglioside conjugatevaccine), GVAX® (prostate cancer vaccine),halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGM-101,IL-13-PE^(38,) IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafamib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, ribimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13, (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®(temozolormide), tesmilifene, thalidomide, THERATOPE® (STn-KLH),thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (besentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 anitbody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zorubicin and the like.

Data

Determination of the utility of compounds having Formula (I) as bindersto and inhibitors of anti-apoptotic Bcl-2 proteins was performed usingthe Time-Resolved-Fluorescence Resonance Energy Transfer (TR-FRET)Assay. Tb-anti-GST antibody was purchased from Invitrogen (Catalog No.PV4216.

Probe Synthesis

All reagents were used as obtained from the vendor unless otherwisespecified. Peptide synthesis reagents including diisopropylethylamine(DIEA), dichloromethane (DCM), N-methylpyrrolidone (NMP),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), N-hydroxybenzotriazole (HOBt) and piperidine were obtained fromApplied Biosystems, Inc. (ABI), Foster City, Calif. or AmericanBioanalytical, Natick, Mass. Preloaded 9-Fluorenylmethyloxycarbonyl(Fmoc) amino acid cartridges (Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH,Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Phe-OH, Fmoc-Gly-OH,Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH,Fmoc-Met-OH, Fmoc-Asn(Trt)-OH, Fmoc-Pro-OH, Fmoc-Gln(Trt)-OH,Fmoc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH,Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH were obtained from ABI or Anaspec,San Jose, Calif. The peptide sysnthesis resin (Fmoc-Rink amide MBHAresin) and Fmoc-Lys(Mtt)-OH, were obtained from Novabiochem, San Diego,Calif. Single-isomer 6-carboxyfluorescein succinimidyl ester (6-FAM-NHS)was obtained from Anaspec. Trifluoroacetic acid (TFA) was obtained fromOakwood Products, West Columbia, S.C. Thioanisole, phenoltriisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol (DODT) andisopropanol were obtained from Aldrich Chemical Co., Milwaukee, Wis.,Matrix-assisted laser desorption ionization mass-spectra (MALDI-MS) wererecorded on an Applied Biosystems Voyager DE-PRO MS). ElectrosprayMass-spectra (ESI-MS) were recorded on Finnigan SSQ7000 (Finnigan Corp.,San Jose, Calif.) in both positive and negative ion mode.

General Procedure for Solid-Phase Peptide Synthesis (SPPS)

peptides were synthesize with, at most 250 μmol preloaded Wangresin/vessel on an ABI 433A peptide synthesizer using 20 μmol scaleFastmoc™ coupling cycles. Preloaded cartridges containing 1 mmolstandard Fmoc-amino acids, except for the position of attachment of thefluorophore, where 1 mmol Fmoc-Lys(Mtt)-OH was placed in the cartridge,were used with conductivity feedback monitoring. N-terminal acetylationwas accomplished by using 1 mmol acetic acid in a cartridge understandard coupling conditions.

Removal of 4-methyltrityl (Mtt) from Lysine

The resin from the syntesizer was washed thrice with dichloromethane andkept wet. 150 mL of 95:4:1dichloromethane:triisopropylsilane:trifluoroacetic acid was flowedthrough the resin bed over 30 minutes. The mixture turned deep yellowthen faded to pale yellow. 100 mL of N,N-dimethylformamide was flowedthrough the bed over 15 minutes. The resin was then washed thrice withN,N-dimethylformamide and filtered. Ninhydrin tests showed a strongsignal for primary amine.

Resin Labeling with 6-Carboxyfluorescein-NHS (6-FAM-NHS)

The resin was treated with 2 equivalents 6-FAM-NHS in 1%DIEA/N,N-dimethylformamide and stirred or shaken at ambient temperatureovernight. When complete, the resin was drained, washed thrice with N,N-dimethylformamide, thrice with (1×DCM and 1×methanol) and dried toprovide an orange resin that was negative by ninhydrin test.

General Procedure for Cleavage and Deprotection of Resin-Bound Peptide

Peptides were cleavfed from the resin by shaking for 3 hours at ambienttemperature in a cleavage cocktail consisting of 80% TFA, 5% water, 5%thioanisole, 5% phenol, 2.5% TIS, and 2.5% EDT (1 mL/0.1 g resin). Theresin was removed by filtration and rinsing twice with TFA. The TFA wasevaporated from the filtrates, and product was precipitated with ether(10 mL/0.1 g resin), recovered by centrifugation, washed twice withether (10 mL/0.1 g resin) and dried to give the crude peptide.

General Procedure for Purification of Peptides

The crude peptides were purified on a Gilson preparative HPLC systemrunning Unipoint® analysis software (Gilson, Inc., Middleton, Wis.) on aradial compression column containing two 25×100 mm segments packed withDelta-Pak™ C18 15 μm particles with 100 Å pore size and eluted with oneof the gradient methods listed below. One to two milliliters of crudepeptide solution (10 mg/mL in 90% DMSO/water) was purified perinjection. The peaks containing the product(s) from each run were pooledand lyophilized. All preparative runs were run at 20 mL/min with eluentsas buffer A: 0.1% TFA-water and bufferB: acetonitrile.

General Procedure for Analytical HPLC

Analytical HPLC was performed on a Hewlett-Packard 1200 series systemwith a diode-array detector and a Hewlett-Packard 1046A fluorescencedetector running HPLC 3D ChemStation software version A.03.04(Hewlett-Packard, Palo Alto, Calif.) on a 4.6×25 mm YMC column packedwith ODS-AQ 5 μm particles with a 120 Å pore size and eluted with one ofthe gradient metnhods listed below after preequilibrating at thestarting conditions for 7 minutes. Eluents were buffer A: 0.1% TFA-waterand buffer B: acetonitrile. The flow rate for all gradients was 1mL/min.

F-Bak: Peptide Probe Acetyl-(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)-(SEQ IDNO: 2)INR-NH₂

Fmoc-Rink amide MBHA resin was extended using the general peptidesynthesis procedure to provide the protected resin-bound peptide (1.020g). The Mtt group was removed, labeled with 6-FAM-NHS and cleaved anddeprotected as described hereinabove to provide the crdue product as anorange solid (0.37 g). This product was purified by RP-HPLC. Fractionsacross the main peak were tested bgy analytical RP-HPLC, and the purefractions were isolated and lyophilized, with the major peak providingthe title compound (0.0802 g) as a yellow solid; MALDI-MS m/z=2137.1[(M+H)⁺].

Alternative Synthesis of Peptide Probe F-Bak: Acetyl-(SEQ ID NO:1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO:2)INR-NH₂

The protected peptide was assembled on 0.25 mmol fmoc-Rink amide MBHAresin (Novabiochem) on an Applied Biosystems 433A automated peptidesynthesizer running Fastmoc™ coupling cycles using pre-loaded 1 mmolamino acid cartridges, except for the fluorescein(6FAM)-labeled lysine,where 1 mmol Fmoc-Lys(4-methyltrityl) was weighed into the cartridge.The N-terminal acetyl group was incorporated by putting 1 mmol aceticacid in a cartridge and coupling as described hereinabove. Selectiveremoval of the 4 -methyltrityl group was accomplished with a solution of95:4:1 DCM:TIS:TFA (v/v/v) flowed through the resin over 15 minutes,followed by quenching with a flow of dimethylformamide. Single-isomer6-carboxyfluorescein-NHS was reacted with the lysine side-chain in 1%DIEA in N,N-dimethylformamide and confirmed complete by ninhydrintesting. The peptide was cleaved from the resin and side-chainsdeprotected by treating with 80:5:5:5:2.5:2.5TFA/water/phenol/thioanisole/triisopropylsilane:3,6/dioxa-1,8-octanedithiol (v/v/v/v/v/v), and the crude peptide wasrecovered by precipitation with diethyl ether. The crude peptide waspurified by reverse-phase high perforntance liquid chromatography, andits purity and identity were confirmed by analytical reverse-phasehigh/performance liquid chromatography and matrix.assistedlaser-desorption mass spectrometry (m/z 2137.1 ((M+H)⁺)).

Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay

Representative compounds were serially diluted in dimethyl sulfoxide(DM5O) starting at 50 μM (2× starting concentration; 10% DMSO) and 10 μLwere transferred into a 384-well plate. Then 10 μL of aprotein/probe/antibody mix was added to each well at finalconcentrations listed in TABLE 1. The samples are then mixed on a shakerfor 1 minute and incubated for an additional 3 hours at roomtemperature. For each assay, the probe antibody andprotein/probe/antibody were included on each assay plate as negative andpositive controls, respectively. Fluorescence was measured on theEnvision (Perkin Elmer) using a 340/35 nm excitation filter and 520/525(F-Bak peptide) and 495/510 nm (Tb-labeled anti-Histidine antibody)emission filtes. Inhibition constants (Ki) are shown in TABLE 2 belowand were determined using Wang's equation (Wang Z.-X An ExactMathematical Expression For Describing Competitive Binding Of TwoDifferent Ligands To A Protein Molecule, FEBS Lett. 1995, 360:111-4).

TABLE 1 Protein, Probe And Antibody Used For TR-FRET  Assays Pro- Anti-Pro- tein Probe Anti- body tein Probe (nM) (nM) body (nM) GST-F-Bak Peptide  1 100 Tb- 1 Bcl-2 Probe Acetyl-(SEQ  anti- ID NO: 1 GSTGQVGRQLAIIGDK(6- FAM) SEQ ID NO: 2 INR-amide) 6-FAM =6-carboxyfluorescein.; Tb = terbium; GST = glutathione S-transferase

The samples were then mixed on a shaker for 1 minute and incubated foran additional 3 hours at room temperature. For each assay, theprobe/antibody and protein/probe/antibody were included on each assayplate as negative and positive controls, respectively. Fluorescence wasmeasured on the Envision (Perkin Elmer) using a 340/35 nm excitationfilter and 520/525 (F-Bak peptide) and 495/510 nm (Tb-labeledanti-Histidine antibody) emission filters.

Inhibition constants (K_(i)) for compounds according to the inventionare shown in TABLE 2 below. Where the K_(i) for a compound isrepresented as “>” (greater than) a certain numerical value, it isintended to mean that the binding affinity value is greater than thelimits of detection of the assay used. Where the K_(i) for a compound isrepresented as “<” (less than) a certain numerical value, it is intendedto mean that the binding affinity value is lower than the limit ofdetection of the assay used.

TABLE 2 TR-FRET Bcl-2 Binding Ki (μM) TR-FRET Example Binding: Bcl-2 No.Ki (μM) 1 0.008354 2 0.031467 3 0.000827 4 0.002474 5 0.000746 60.000787 7 0.002592 8 0.003451 9 0.000754 10 0.00072  11 0.000171 120.000331 13 0.001621 14 0.000079 15 0.000586 16 0.003039 17 0.005578 180.002487 19 0.001679 20 0.003965 21 0.014054 22 0.005455 23 0.00827  240.014984 25 0.001501 26 0.000511 27 0.002212 28 0.001326 29 0.000903 300.000071 31 0.002007 32 0.001584 33 0.007173 34 0.000049 35 0.000022 360.00007  37 0.000005 38 0.000013 39 0.000019 40 0.000019 41 0.000027 420.00003  43 0.000034 44 0.000036 45 0.000047 46 0.000047 47 0.00005  480.000053 49 0.000062 50 0.000062 51 0.000066 52 0.000072 53 0.000077 540.000082 55 0.00009  56 0.000106 57 0.000147 58 0.000155 59 0.000184 600.000187 61 0.00022  62 0.000227 63 0.000438 64 0.000458 65 0.00052  660.000592 67 0.000807 68 0.005934 69 0.008246 70 0.020421 71 0.031597 720.031666 73 0.03226  74 0.18943  75 0.076832 76 0.2395  77 0.45052 78 >1.195000   79 0.099826 80 0.14872  81 0.031048 82 0.51156 83 >1.195000   84 0.013654 85 0.005626 86 0.005263 87 0.26427 88 >1.195000   89 0.006111 90 0.010626 91 >1.195000   92 0.002569 930.01683  94 0.56121  95 0.000428 96 >1.195000   97 0.14659  98 0.00095999 0.071364 100 0.11299  101 0.6695  102 0.043518 103 0.006755 1040.002321 105 0.003567 106 0.21452  107 0.000331 108 nd 109 0.000237 1100.000039 111 0.01744  112 0.000042 113 0.000032 114 0.000036 1150.000042 116 0.000123 117 0.000072 118 0.000151 119 0.000156 1200.000214 121 0.000081 122 <0.000001   123 0.00011  124 0.000033 1250.000075 126 0.000068 127 0.00003  128 0.000064 129 0.000107 1300.000067 131 0.000066 132 0.000211 133 0.000055 134 0.000181 1350.000068 136 0.000177 137 0.000021 138 0.000016 139 0.000125 1400.000223 141 0.000482 142 0.000071 143 0.000053 144 0.000028 1450.000057 146 0.00004  147 0.000127 148 0.000106 149 0.00003  1500.000759 151 0.006935 152 0.018589 154 0.000012 155 0.000062 1560.000035 157 0.00072  158 0.000619 159 0.000526 160 0.000028 1610.000031 162 0.000048 163 0.000686 164 0.000056 165 0.00012  1660.000082 167 0.001345 168 0.028343 169 0.000498 170 0.000036 1710.000066 172 0.000549 173 0.000019 174 0.000037 175 0.000046 1760.00024  177 0.000037 178 0.000175 179 0.000036 180 0.000112 1810.000119 182 0.000172 183 0.00253  184 0.000155 185 0.000083 1860.000035 187 0.000054 188 0.000073 189 0.000036 190 0.000077 1910.000552 192 0.000024 193 0.000064 194 0.000317 195 0.000684 1970.00022  198 <0.000010   199 0.000244 200 0.000081 201 0.000001 2020.020043 203 0.000084 204 0.000075 205 0.000153 206 0.000037 2070.000074 208 0.000261 209 <0.000010   210 0.00002  211 0.001338 2120.000375 213 0.000031 214 0.000221 215 0.002954 216 0.000027 2170.000174 218 0.000175 219 0.014857 220 0.000127 221 0.000227222 >1.195000   223 0.010911 224 0.005603 225 0.003283 226 0.007586 2270.000174 229 0.001085 230 0.002833 231 0.036946 232 0.001047 2330.000037 234 0.000099 235 0.000039 236 0.000071 237 0.000197 2380.000124 239 0.000105 240 0.000912 241 0.000141 242 0.000092 2430.000069 244 0.001734 245 0.00048  246 0.000065 247 0.000039 2480.000051 249 0.000168 250 0.000672 251 0.000435 252 0.001147 2530.00005  254 0.000119 255 0.007013 256 0.000105 257 0.000097 2580.000083 259 0.000165 260 0.011834 261 0.000186 262 0.000276 2630.00011  264 0.000068 265 0.000363 266 0.00081  267 0.028426 2680.000042 269 0.000469 270 >1.195000   271 0.001908 272 0.00124  2730.000516 274 0.000936 275 0.000081 276 0.000199 277 0.000017 2780.039967 279 0.001703 280 0.00755  281 0.000111 282 0.001012 2830.01721  284 0.079348 285 0.000037 286 0.003181 287 0.000131 2880.000017 289 <0.000010   290 0.000251 291 0.000273 292 0.000191 2930.000233 294 0.000127 295 0.000077 296 <0.000010   297 <0.000010   2980.000054 299 0.051687 300 0.013659 301 0.000113 302 <0.000010   3030.000092 304 0.000822 305 0.000146 306 0.000671 307 0.000524 3080.00004  309 0.00069  310 0.000155 311 0.000185 312 0.000531 313<0.000010   314 0.003094 315 0.004555 316 0.000058 317 0.000205 318<0.000010   319 0.000198 320 0.000028 321 0.000029 322 0.00453  3230.003484 324 <0.000010   325 0.000183 326 0.000037 327 0.000212 3280.000068 329 0.000108 330 <0.000010   331 0.000238 332 0.000034 3330.000107 334 0.000197 335 <0.000010   336 <0.000010   337 0.000049 338<0.000010   339 0.000057 340 0.000385 341 0.000017 342 0.003340 3430.000009 344 0.000042 345 0.000005 346 <0.000010   347 0.000377 3480.003779 349 0.000019 350 <0.000010   351 0.002843 352 0.000079 3530.000016 354 0.000114 355 0.009567 356 0.002822 357 0.000177 3580.000062 359 0.000110 360 0.000050 361 0.000015 362 0.000033 363<0.000010   364 0.000014 365 0.004551 366 0.006052 367 0.000012 368<0.000010   369 0.000014 370 <0.000010   371 <0.000010   372 0.014978373 1.195000 374 0.005337 375 0.327810 376 0.057705 377 0.002323 378<0.000010   379 0.017948 380 0.008274 381 0.000020 382 0.000114 3830.427490 384 0.006233 385 0.049293 386 <0.000010   387 <0.000010   3880.000020 389 <0.000010   390 <0.000010   391 <0.000010   392 <0.000010  393 <0.000010   394 0.000018 395 0.000077 396 <0.000010   397 0.000137398 0.000175 399 <0.000010   400 0.000082 401 0.000035 402 0.000039 4030.002136 404 0.000069 405 0.000354 406 0.000166 407 0.000946 4080.001160 409 0.000686 410 <0.000010   411 0.021291

The inhibition at constant (K_(i)) is the dissociation constant at anenzyme-inhibitor complex or a protein/small molecule complex, whereinthe snanil molecule is inhibiting binding of one protein to anotherprotein. So a large K_(i) value indicates a low binding affinity and asmall K_(i) value indicates a high binding affinity.

The data in TABLE 2 shows inhibition constants for the inhibition of aBak BH3 peptide probe to Bcl-2 and indicate that compounds according tothe invention have high binding affinities for anti-apoptotic Bcl-2protein. The compounds are therefore expected to have utility intreatment of diseases during which anti-apoptotic Bcl-2 protein isexpressed.

It is expected that, because compounds having Formula I bind to Bcl-2,they would also have utility as binders to anti-apoptotic proteinshaving close structural homology to Bcl-2, such as, for example,anti-apoptotic Bcl-2 , Bcl-X_(L), Mcl-1 and BFl-1/A1 proteins.

Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breastcancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicualr lymphoma, lymphoid malignancies ofT-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small cell lung cancer, prostate cancer,small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer splee cancer, and the like is described in commonly-owned PCT US2004/36770, published as WO 2005/049593, and PCT US 2004/37911,published as WO 2005/024636.

Involvement of Bcl-2 proteins in immune and autoimmune diseases isdescribed in Current Allergy and Asthma Reports 2003, 3, 378-384;British Journal of Haematology 2000, 110 (3), 584-90; Blood 2000, 95(4), 1283-92; and New England Journal of Medicine 2004, 351(14),1409-1418.

Involvement of Bcl-2 proteins in arthritis is disclosed incommonly-owned U.S. Provisional Patent Application Ser. No. 60/988,479.

Involvement of Bcl-2 proteins in bone marrow transplant rejection isdisclosed in commonly-owned U.S. patent application Ser. No. 11/941,196.

Overexpression of Bcl-2 proteins correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem. Cancers include, but are not limited to, hematologic and solidtumor types such as acoustic neuroma, acute leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia (monocytic,myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocyticand promyelocytic), acute t-cell leukemia, basal cell carcinoma, bileduct carcinoma, bladder cancer, brain cancer, breast cancer (includingestrogen-receptor positive breast cancer), bronchogenic carcinoma,Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordoma,choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronicmyelocytic (granulocytic) leukemia, chronic myelogenous leukemia, coloncancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, gastric carcinoma, germ cell testicular cancer,gestational trophobalstic disease, glioblastoma, head and neck cancer,heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer,hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lungcancer (including small cell lung cancer and non-small cell lungcancer), lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblasticleukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma,follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma),malignancies and hyperproliferative disorders of the bladder, breast,colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoidmalignancies of T-cell or B-cell origin, leukemia, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma,oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer,pancreatic cancer, papillary adenocarcinomas, papillary carcinoma,peripheral T-cell lymphoma, pinealoma, polyeythemia vera, prostatecancer (including hormone-insensitive (refectory) protstate cancer),rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma,sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small celllung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer,squamous cell carcinoma, synovioma, sweat gland carcinoma, testicularcancer (including germ cell testicular cancer), thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer,Wilms' tumor and the like.

It is also expected that compounds having Formula (I) would inhibitgrowth of cells expressing Bcl-2 proteins derived from a pediatriccancer or neoplasm including embryonal rhabdomyosarcoma, pediatric acutelymphoblastic leukemia, pediatric acute myelogenons leukemia, pediatricalveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatricanaplastic large cell lymphoma, pediatric anaplastic medulloblastoma,pediatric atypical teratoid/rhabdoid tumor of the central nervoussystem, pediatric biphenotypic acute leukemia, pediatric Burkittslymphoma, pediatric cancers of Ewing's family of tumors such asprimitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm'stumor, pediatric favorable histology Wilm's tumor, pediatricglioblastoma, pediatric medulloblastoma, pediatric neuroblastoma,pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cellcancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoidkidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancerssuch as lymphoma and skin cancer and the like.

Autoimmune disorders include acquired immunodeficiency disease syndrome(AIDS), autoimmune lymphoproliferativc syndrome, hemolytic anemia,inflammatory diseases, and thrornbocytopcnia, acute or chronic immunedisease associated with organ transplantation, Addison's disease,allergic diseases, alopecia, alopecia areata, atheromatousdisease/arteriosclerosis, atherosclerosis, arthritis (includingosteoarthritis, juvenile chronic arthritis, septic arthritis, Lymearthritis, psoriatic arthritis and reactive arthritis), autoimmunebullous disease, abetalipoprotemia, acquired immunodeficiency-relateddiseases, acute immune disease associated with organ transplantation,acquired acrocyanosis, acute and chronic parasitic or infectiousprocesses, acute pancreatitis, acute renal failure, acute rheumaticfever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats,adult (acute) respiratory distress syndrome, AIDS dementia complex,alcoholic cirrhosis, alcohol-induced liver injury, alcohol-inducedhepatitis, allergic conjunctivitis, allergic contact dermatitis,allergic rhinitis, allergy and asthma, allograft rejection,alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateralsclerosis, anemia, angina pectoris, ankylosing spondylitis associatedlung disease, anterior horn cell degeneration, antibody mediatedcytotoxicity, antiphospholipid syndrome, anti-receptor hypersensitivityreactions, aortic and peripheral aneurysms, aortic dissection, arterialhypertension, arteriosclerosis, arteriovenous fistula, arthropathy,asthma, asthma, ataxia, atopic allergy, atrial fibrillation (sustainedor paroxysmal), atrial flutter, atrioventricular block, atrophicautoimmune hypothyroidism, autoimmune haemolytic anaemia, autoimmunehepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoidhepatitis), autoimmune mediated hypoglyecemia, autoimmune neutropaenia,autoimmune thrombocytopaenia, autoimnmune thyroid disease, B celllymphoma, bone graft rejection, bone marrow transplant (BMT) rejection,bronchiolitis obliterans, bundle branch block, burns, cachexia, cardiacarrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy,cardiopulmonary bypass inflammation response, cartilage transplantrejection, cerebellar cortical degenerations, cerebellar disorders,chaotic or multifocal atrial tachycardia, chemotherapy associateddisorders, chlamydia, choleosatatis, chronic alcoholism, chronic activehepatitis, chronic fatigue syndrome, chronic immune disease associatedwith organ transpianration, chronic eosinophilic pneumonia, chronicinflammatory pathologies, chronic mucocutaneous candidiasis. chronicobstructive pulmonary disease (COPD), chronic salicylate intoxication,colorectal common varied immunodeficieney (common variablehypogammaglobulinaemia), conjunctivitis, connective tissue diseaseassociated interstitial lung disease, contact dermatitis, Coombspositive haemolytic anaemia, cor pulmonale, Creutzfeldt-Jakob disease,cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis,culgture negative sepsis, cystic fibrosis, cytokine therapy associateddisorders, Crohn's disease, dementia pugilistica, demyelinatingdiseases, dengue hemorrhagic fever, dermatitis scleroderma, dermatologicconditions, dermatomyositis/polymyositis associated lung disease,diabetes, diabetic arteriosclerotic disease, diabetes mellitus, DiffuseLewy body disease, dilated cardiomyopathy, dilated congestivecardiomyopathy, discoid lupus erythematosus, disorders of the basalganglia, disseminated intravascular coagulation, Down's Syndrome inmiddle age, drug-induced interstitial lung disease, drug-inducedhepatitis, drug-induced movement disorders induced by drugs which blockCNS dopamine, receptors, drug sensitivity, eczema encephalomyelitis,endocarditis, endocrinopathy, enteropathic synovitis, epiglottitis,Epstein-Barr virus infection, erythromelalgia, extrapyramidal andcerebellar disorders, familial hematophagocytic lymphohistiocytosis,fetal thymus implant rejection, Friedreich's ataxia, functionalperipheral arterial disorders, femal infertility, fibrosis, fibroticlung disease, fungal sepsis, gas gangrene, gastric ulcer, giant cellarteritis, glomerular nephritis, glomerulonephritides, Goodpasture'ssyndrome, goitrous autoimmune hypothroidism (Hashimoto's disease), goutyarthritis, graft rejection of any organ or tissue, graft versus hostdisease, gram negative sepsis, gram positive sepsis, granulomas due tointracellular organisms, group B streptocci (GBS) infection, Grave'sdisease, heaemosiderosis associated lung disease, hairy cell leukemia,hairy cell leukemia, Hallerrorden-Spatz disease, Hashimoto's throiditis,hay fever, heart transplant rejection, hemachromatosis, hematopoieticmalignancies (leukemia and lymphoma), hemolytic anemia, hemolytic uremicsyndrome/thrombolytic thrombocytopenic purpura, hemorrhage,Henoch-Schoenlein purpurea, Hepatitis A, Hepatitis B, Hepatitis C, HIVinfection/HIV neuropathy, Hodgkin's disease hypoparathyroidism,Huntington's chorea, hyperkinetic movement disorders, hypersensitivityreactions, hypersensitivity pneumonitis, hyperthyroidism, hypokineticmovement disorders, hypothalamic-pituitary-adrenal axis evaluation,idiopathic Addison's disease, idiopathic leucopaenia, idiopathicpulmonary fibrosis, idiopathic thrombocytopaenia, idiosyncratic liverdisease, infantile spinal muscular atrophy, infection diseases,inflammation of the aorta, inflammatory bowel disease, insulin dependentdiabetes mellitus, interstitial pneumonitis, iridocyclitis/uveitis/opticneuritis, ischemia-reperfusion injury, ischemic stroke, juvenilepernicious anaemia, juvenile rheumatoid arthritis, juvenile spinalmuscular atrophy, Kaposi's sarcoma, Kawasaki's disease, kidneytransplant rejection, legionella, leishmaniasis, leprosy, lesions of thecorticospinal system, linear IgA disease, lipidema, liver transplantrejection, Lyme disease, lymphederma, lymphocytic infiltrative lungdisease, malaria, male infertility idiopathic or NOS, malignanthistiocytosis, malignant melanoma, meningitis, meningococcemia,microscopic vasculitis of the kidneys, migraine headache, mitochondrialmultisystem disorder, mixed connective tissue disease, mixed connectivetissue disease associated lung disease, monoclonal gammopathy, multiplemycloma, multiple systems degenerations (Mencel Dejerine-ThomasShi-Drager and Machado-Joseph), myalgic encephalitis/Royal Free Disease,myasthenia gravis, microscopic vasculitis of the kidneys, mycobacteriumavium intracellulare, mycobacterium tuberculosis, myelodyplasticsyndrome, myocardial infarction, myoeardial ischemic disorders,nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis,nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic Imuscular atrophies, neutropenic fever, Non-alcoholic Steatohepatitis,occlusion of the abdominal aorta and its branches, occlusive arterialdisorders, organ transplant rejection, orchitis/epidydimitis,orchitis/vasectomy reversal procedures, organomegaly, osteoarthrosis,osteoporosis, ovarian failure, pancreas transplant rejection, parasiticdiseases, panthyroid transplant rejection, Parkinson's disease, pelvicinflammatory disease, pemphigus vulgaris, pemphigus foliaccus,pemphigoid, perennial rhinitis, pericardial disease, peripheralatherlosclerotic disease, peripheral vascular disorders, peritonitis,pernicious anemia, phacogenic uveitis, pneumocystis carinii pneumonia,pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,monoclonal gammopathy, and skin changes syndrome), post perfusionsyndrome, post pump syndrome, post-MI cardiotomy syndrome,postinfectious interstitial lung disease, premature ovarian failure,primary biliary cirrhosis, primary sclerosing hepatitis, primarymyxoedema, primary pulmonary hypertension, primary sclerosingcholangitis, primary vasculitis, Progressive supranucleo Palsy,psoriasis, psoriasis type 1, psoriasis type 2, psoriatic arthropathy,pulmonary hypertension secondary to connective tissue disease, pulmonarymanifestation of polyarteritis nodosa, post-inflammatory interstitiallung disease, radiation fibrosis, mdiation therapy, Raynaud's phenomenonand disease, Raynoud's disease, Refsum's disease, regular narrow QRStachycardia, Reiter's disease, renal disease NOS, renovascularhypertension, reperfusion injury, restrictive cardiomyopathy, rheumatoidarthritis associated interstitial lung disease, rheumatoid spondylitis,sarcoidosis, Schmidt's syndrome, seleroderma, senile chorea, SenileDementia of Lewy body type, sepsis syndrome, septic shock, seronegativearthropathies, shock, sickle cell anemia, Sjögren's disease associatedlung disease, Sjörgren's syndrome, skin allograft rejection, skinchanges syndrome, small bowel transplant rejection, sperm autoimmunity,multiple sclerosis (all subtypes), spinal ataxia, spinocerebellardegenerations, spondyloarthropathy, spondyloarthopathy, sporadic,polyglandular deficiency type I sporadic, polyglandular deficiency typeII, Still's disease, streptococcal myositis, stroke, structural lesionsof the cerebellum, Subacute sclerosing panencephalitis, sympatheticophthalmai, Syncope, syphilis of the cardiovascular system, systemicanaphylasis, systemic inflammatory response syndrome, systemic onsetjuvenile rheumatoid arthritis, systemic lupus erythematosus, systemiclupus erythematosus-associated lung disease, system sclerosis, systemicsclerosis-associated interstitial lung disease, T-cell or FALL ALL,Takayasu's disease.arteritis, Telangiectasia, Th2 Type and Th1 Typemediated diseases, thromboangitis obliterans, thrombocytopenia,thyroiditis, toxicity, toxic shock syndrome, transplants,trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibodyhepatitis), type B insulin resistance with acanthosis nigricans, typeIII hypersensitivity reactions, type IV hypersensitivity, ulcerativecolitic arthropathy, ulcerative colitis, unstable angina, uremia,urosepsis, urticaria, uveitis, valvular heart diseases, varicose veins,vasculitis, vasculitic diffuse lung disease, venous diseases, venousthrombosis, ventricular fibrillation, vitiligo acute liver disease,viral and funal infections, vital encephalitis/aseptic meningitis,vital-associated hemaphagocytic syndrome, Wegener's granulomatosis,Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection ofany organ or tissue, yersinia and salmonella-associated arthropathy andthe like.

Schemes and Experimentals

The following abbreviations have the meaings indicated. ADDP means1,1′-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of(DHQD)₂PHAL, K₃Fe(CN)₆, K₂CO₃, and K₂SO₄; 9-BBN means9-borabicyclo(3.3.1)nonane; Boc means tert-butoxycarbonyl; (DHQD)₂PHALmeans hydroquinidine 1,4-phthalazinediyl diethyl ether, DBU means1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminumhydride; DIEA means diisopropylethylamine; DMAP meansN,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe means1,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppbmeans 1,4-bis(diphenylphosphino)-butane; dppe means1,2-bis(diphenylphosphino)ethane; dppf means1,1′-bis(diphenylphosphino)ferrocene; dppm means1,1-bis(diphenylphosphino)methane; EDAC-HCl means1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc meansfluorenylmethoxycarbonyl; HATU means O-(7-azabenzotriazol-1-yl)N,N′,N′N′-tetramethyluronium hexafluorophosphate; HMPA meanshexamethylphosphoramide; IPA means isopropyl alcohol; MP-BH₃ meansmacroporous triethylammonium methylpolystyrene cyanoborohydride; TEAmeans triethylamine; TFA means trifluoroacetic acid; THF meanstetrahydrofuran; NCS means N-chlorosuccinimide; NMM meansN-methylmorpholine; NMP means N-methylmorpholine; PPh₃ meanstriphenylphosphine.

The following schemes are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. Compounds of this invendon may bemade by synthetic chemical processes, examples of which are shownherein. It is meant to be understood that the order of the steps in theprocesses may be varied, that reagents, solvents and reaction conditionsmay be substituted for those specifically mentioned, and that vulnerablemoieties may be protected and deprotected, as necessary.

Compounds of Formula (4) can be prepared as shown in SCHEME I, and canbe used as described in SCHEME 8 to prepare compounds of Formula (I),which are representative of the compounds of the present invention,Compounds of Formula (I) wherein R is alkyl, can be converted tocompounds of Formula (2) using Z³L¹MgX¹, wherein X¹ is a halide, in asolvent such as but not limited to ether or tetrahydrofuran. Compoundsof Formula (3) can be prepared from compounds of Formula (2) using astrong base such as NaH and R⁵⁷X², wherein X²is a halide and R⁵⁷ is asdescribed herein. Compounds of Formula (3), when treated with aqueousNa0H or LiOH, will provide compounds of Formula (4).

As shown in SCHEME 2, compounds of Formula (5) can be reacted withcompounds of Formula (6) and a reducing agent to provide compounds ofFormula (7). Examples of reducing agents include sodium borohydride,sodium cyanoborohydride, sodium triacetoxyborohydride, polymer supportedcyanoborohydride, and the like. The reaction is typically performed in asolvent such as but not limited to methanol, tetrahydrofuran, anddichloromethane or mixtures thereof. Compounds of Formula (8) can beprepared from compounds of Formula (7) as described in SCHEME 1, and canbe used as described in SCHEME 8 to prepare compounds of Formula (I).

Compounds of Formula (9), when reaction with a compound a Formula (10)wherein X is a halide or triflate, and a base will provide a compound ofFormula (11). Bases useful in the reaciton include triethylamine,diisopropylethylamine and the like. Compounds of Formula (13), wherein Yis as described herein for substituents on Z³, can be prepared fromcompounds of Formula (11) and compounds of Formula (12) using Suzukicoupling conditions known to those skilled in the art and readilyavailable in the literature. Compounds of Formula (14) can be preparedfrom compounds of Formula (13) as described in SCHEME 1, and can be usedas described in SCHEME 8 to prepare compounds of Formula (I).

As shown in SCHEME 4, compounds of Formula (17) can be prepared fromcompounds of Formula (15) and compounds of Formula (16), wherein R isalkyl and R³⁸ is as described herein, using Suzuki coupling conditionsknown to those skilled in the art and readily available in theliterature. Compounds of Formula (17) can be reduced to compounds ofFormula (18) using a reducing agent such as LiAlH₄ in a solvent such asbut not limited to diethyl ether or THF. Compounds of Formula (19) canbe prepared from compounds of Formula (18) using Dess-Martin periodinaneor Swern oxidation conditions known to those skilled in the art andreadily available in the literature. Compounds of Formula (19) can bereacted with a compound of Formula (5) and a reducing agent to providecompounds of Formula (20). Examples of reducing agents include sodiumborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride,polymer supported cyanoborohydride, and the like. The reaction istypically performed in a solvent such as but not limited to methanol,tetrahydrofuran, 1,2-dichloroethane, and dichloromethane or mixturesthereof. Compounds of Formula (21) can he prepared from compounds ofFormula (20) as described in SCHEME 1, and can be used as described inSCHEME B to prepare compounds of Formula (I).

As shown in SCHEME 5, compounds of Formula (22), wherein R is alkyl, maybe converted to compounds of Formula (23) by reacting the former,wherein X¹ is Cl, Br, I, or CF₃SO₃—, and compounds of Formula R⁴¹—OH anda catalyst, with or without a first base. Examples of catalysts includecopper(I) trifluoromethanesulfonate toluene complex, PDCl₂, Pd(OAc)₂,and Pd₂(dba)₃. Examples of first bases include triethylamine,N,N-diisopropylethylamine, Cs₂CO₃, Na₂CO₃, K₃PO₄, and mixtures thereof.

Compounds of Formula (22) may also be converted to compounds of Formula(23) by reacting the former, when X¹ is Cl, F, or NO₂, and compounds ofFormula R⁴¹—OH with a first base. Examples of first bases includetriethylamine, N,N-diisopropylethylamine, Cs₂CO₃, Na₂CO₃, K₃PO₄, andmixtures thereof.

Compounds of Formula (18) can be reacted with mesyl chloride and a basesuch as but not limited to triethylamine, followed byN-t-butoxycarbonylpiperazine, to provide compoundes of Formula (24).Compounds of Formula (25) can be prepared by reacting compounds ofFormula (24) with triethylsilane and trifluoroacetic acid. Compounds ofFormula (25) can be reacted with compounds of Formula (26) and HK₂PO₄ toprovide compounds of Formula (27) in a solvent such as but not limitedto dimethylsulfoxide. Compounds of Formula (28) can be prepared fromcompounds of Formula (27) as described in SCHEME 1, and can be used asdescribed in SCHEME 8 to prepare compounds of Formula (I).

As shown in SCHEME 7, compounds of Formula (I) can be reacted with anappropriate triphenylphosphonium bromide of Formula (29) and a base suchas but not limited to sodium hydride or n-butyllithium to providecompounds of Formula (30). The reaction is typically performed in asolvent such as THF or DMSO. Compounds of Formula (31) can be preparedfrom compounds of Formula (30) as described in SCHEME 1, and can be usedas described in SCHEME 8 to prepare compounds of Formula (I).

As shown in SCHEME 8, compounds of Formula (32), which can be preparedas described herein, may be converted to compounds of Formula (33) byreacting the former with ammonia. Compounds of Formula (33) may beconverted to compounds of Formula (I) by reacting the former andcompounds of Formula (4), (8), (14), (21), (28), (31), or (38) and acoupling agent, with or without a first base. Examples of couplingagents include 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimidehydrochloride. 1,1′-carbonyldiimidazole, andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.Examples of first bases include triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixturesthereof.

Compounds of Formula (33), prepared as described in SCHEME (8), may alsobe convened to compounds of Formula (I) by reacting the former andcompounds of Formula (34) and a first base. Examples of first basesinclude but are not limited to sodium hydride, triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixturesthereof.

As shown m SCHEME 10, compounds of Formula (35), wherein L is a bond,alkyl, O, S, S(O), S(O)₂, NH, etc., can be reacted with compounds orFormula (36), to provide compounds of Formula (37). The reaction istypically performed at elevated temeratures in a solvent such as but notlimited to dimethylsulfoxide, and may require the use of a base such asbut not limited to potassium phosphate, potassium carbonate, and thelike. Compounds of Formula (38) can be prepared from compounds ofFormula (37) as described in SCHEME 1, and can be used as described inSCHEME 8 to prepare compounds of Formula (I).

Compounds of Formula (39), wherein Y is as described herein forsubstituents on Z³, can be prepared from compounds of Formula (39A)wherein X is a halide or triflate, and Y-B(OH)₂ using Suzuki couplingconditions known to those skilled in the art and readily available inthe literature. Compounds of Formula (39) can be reacted with tert-butylpiperazine-1-carboxylate and a reducing agent such as sodiumtriacetoxyborohydride to provide compounds of Formula (40). The reactionis typically performed in a solvent such as but not limited to methylenechloride. Compounds of Formula (41) can be prepared from compounds ofFormula (40) by reacting the latter with R⁵⁷X, wherein X is a halide,and NaH in a solvent such as N,N-dimethylformamide, and then theresulting material can be treated with triethylsilane andtrifluoroacetic acid in dichloromethane. Compounds of Fonnula (41) canbe used as described in Scheme 10 wherein L¹-Z³ is as shown in Formula(41).

As shown in SCHEME 12, substituted piperazin-2-ones wherein R⁵⁷ isalkyl, can be reacted with compounds of Formula (6) and a reducing agentsuch as sodium triacetoxyborohydride in dichloromethane to providecompounds of Formula (42). Compounds of Formula (42) can be reduced tocompounds of Formula (43) using a reducing agent such as but not limitedto lithium aluminum hydride in a solvent such as but not limited totetrahydrofuran. Compounds of Formula (43) can be used as described inScheme 10 wherein L¹-Z³ is as shown in Formula (43).

The following examples are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. The exemplified compounds werenamed using ACO/ChemSketch Version 5.06 (5 Jun. 2001, Advanced ChemistryDevelopment Inc., Toronto, Ontario), or ChemDraw® Vet 9.0.5(CambridgeSoft, Cambridge, Mass.). Intermediates were named usingChemDraw® Vet. 9.0.5 (CambridgeSoft, Cambridge, Mass.).

EXAMPLE 14-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 1A tert-butyl4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-carboxylate

4′-Chlorobiphenyl-2-carboxaldehyde (4.1 g), tert-butylpiperazine-1-carboxylate (4.23 g) and sodium triacetoxyborohydride (5.61g) in CH₂Cl₂ (60 mL) were stirred for 24 hours. The mixture was treatedwith methanol and poured into ether. The extract was washed with waterand brine and concentrated. The concentrate was chromatographed onsilica gel with 2-25% ethyl acetate/hexanes.

EXAMPLE 1B 1-((4′-chlorobiphenyl-2-yl)methyl)piperazine

EXAMPLE 1A (3.0 g) and triethylsilane (1 mL) were stirred indichloromethane (30 mL) and trifluoroacetic acid (30 mL) for 2 hours.The mixture was concentrated, taken up in ether and concentrated again.

EXAMPLE 1C methyl2-bromo-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

Methyl 2-bromo-4-fluorobenzoate (3 g), EXAMPLE 1B (4.43 g), and K₂CO₃(3.56 g) were stirred in DMSO (35 mL) at 125° C. for 24 hours. Themixture was cooled, taken up in ethyl acetate (500 mL), washed withwater and brine, dried over Na₂SO₄, filtered and concentrated. Theconcentrate was chromatographed on sibca gel with 5-25% ethyl acetatehexanes.

EXAMPLE 1D 3-((dimethylamino)methyl)phenol

3-Hydroxybenzaldehyde (1.0 g), 2M dimethylamine in THF (5 mL), andsodium triacetoxyborohydride (2 g) in CH₂Cl₂ (10 mL) were stirred for 24hours. The mixture was treated with methanol and chromatographed onsilica gel with 2-25% ethyl acetate/hexanes.

EXAMPLE 1E methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((dimethylamino)methyl)phenoxy)benzoate

EXAMPLE 1C (400 mg), EXAMPLE 1D (260 mg), Cs₂CO₃ (570 mg), 1-naphtoicacid (2.96 g), copper (1) triflate-toluene complex (245 mg), ethylacetate (9 μL), and 4 Å sieves (30 mg) in toluene (2 mL) was stirred at105° C. for 24 hours. The mixture was cooled and taken up in ethylacetate (100 mL) and water (40 mL). The layers were separated and theextract was washed twice with Na₂CO₃ solution and brine, dried, andconcentrated. The concentrate was chromatographed on silica gel with25-50% ethyl acetate/hexanes.

EXAMPLE 1F4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((dimethylamino)methyl)phenoxy)benzoicacid

EXAMPLE 1E (750 mg) was stirred in 25 mL 2:1 dioxane/1 M NaOH at 80° C.for 4 hours. The solution was cooled and adjusted to pH 4 with NaH₂PO₄solution and concentrated HCl, and extracted with ethyl acetate. Theextract was washed with brine, dried (Na₂SO₄), and concentrated.

EXAMPLE 1G3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyiamino)benzenesulfonamide

4-Fluoro-3-nitrobenzenesulfonamide (2.18 g),(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) werestirred in THF (30 mL) for 24 hours. The solution was diluted with ethylacetate, washed with NaH₂PO₄ solution and brine, and dried (Na₂SO₄),filtered and concentrated. The product was triturated from ethylacetate.

EXAMPLE 1H 4-(4-((4′-chloro-1-biphenyl-2-yl)methyl)piperszin-1-yl)-2-(3-((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

EXAMPLE 1F (128 mg), EXAMPLE 1G (73 mg),1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride (88 mg),and 4-dimethylaminopyridine (28 mg) were stirred in CH₂Cl₂ (3 mL) for 24hours. The mixture was cooled and chromatographed on silica gel with0-10% methanol/ethyl acetate. ¹H NMR (300 MHz, DMSO-d₆) δ 11.15 (br s,1H), 8.63 (dd, 1H), 8.49 (d, 1H), 7.80 (dd, 1H), 7.44-7.53 (m, 5H),107.36 (m, 3H), 7.22 (m, 3 H), 7.01 (s, 1H), 6.92 (d, 1H), 6.78 (d, 1H),6.44 (s, 1H), 4.17 (m, 2H), 3.86 (dd, 2H), 3.33 (m, 6H), 3.16 (m, 4H),2.66 (s, 6H), 2.37 (br s, 4H), 1.91 (m, 1H), 1.63 (d, 2H), 1.29 (m, 2H).

EXAMPLE 24-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylamino)methyl)phenoxy)-N((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 2A 3-(methylamino)phenol

Ethylamine was bubbled into a solution of 4-hydroxybenzaldehyde (2.0 g)and sodium triacetoxyborohydride (5.2 g) in CH₂Cl₂ (60 mL) for 12 hour,and the mixture was stoppered and stirred for 24 hours. 1M NaOH solutionwas added (10 mL), and di-tert-butyl dicarbonate (3.57 g) andtriethylamine (2.28 mL) were then added and the mixture was stirred for24 hours. The solution was cooled and adjusted to pH 4 with NaH₂PO₄solution and concentrated HCl, and extracted with ethyl acetate. Theextract was washed with brine, dried (Na₂SO₄), and concentrated. Theconcentrate was chromatographed on silica gel with 20% ethylacetate/hexanes.

EXAMPLE 2B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylamino)phenoxy)benzoate

EXAMPLE 1C (457 mg), EXAMPLE 2A (225 mg), cesium carbonate (595 mg),copper(1) triflate toluene complex (41 mg), and ethyl acetate (0.016 mL)in toluene (5 mL) were stirred at 110° C. for 72 hours. The mixture wascooled and chromatographed on silica gel with 5-25% ethylacetate/hexanes.

EXAMPLE 2 C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylamino)phenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 2B for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 2D4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylamino)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 2C for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (500 MHz, DMSO-d₆) δ 11.60 (br s, 1H), 8.37 (s, 1H),7.69 (d, 1H), 7.58 (d, 1H), 7.47 (m, 5H). 7.38 (m, 3 H), 7.24 (m, 1H)6.95 (d, 1H), 6.89 (dd, 1H), 6.61 (d, 1H), 6.26 (s, 1H), 6.13 (d, 1H),5.97 (s, 1H), 5.92 (d, 1H), 5.59 (br s, 1H), 3.84 (dd, 2H), 3.37 (m,6H), 3.03 (m, 4H), 2.89 (m, 2H), 2.59 (br s, 3 H), 2.36 (br s, 4H), 1.91(m, 1H), 1.62 (d, 2H), 1.24 (m, 2H).

EXAMPLE 3

-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((1-(methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

EXAMPLE 3A ethyl 4-fluoro-2-(2-methyl-1H-indol-5-yloxy)benzoate

Ethyl 2,4-difluorobenzoate (1.14 g), K₃PO₄ (1.30 g) and2-methyl-5-indolol (0.90 g) were stirred at 110° C. in diglyme (12 mL)for 24 hours. The mixture was cooled and poured into ether. The solutionwas washed three times with 1M NaOH solution, and with brine, and dried.The solution was then concentrated. The concentrate was chromatographedon silica gel with 10% ethyl acetate/hexanes.

EXAMPLE 3B methyl4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

to a suspension of hexane-washed NaH (17 g) in dichloromethane (700 mL)was added 5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwiseat 0° C. After stirring for 30 minutes, the mixutre was cooled to −78°C. and trifluoroacetic anhydride (40 mL) was added. The mixture waswarmed to room temperature and stirred for 24 hours. The extract waswashed with brine, dried and concentrated.

EXAMPLE 3C methyl2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

EXAMPLE 3B (62.15 g) 4-chlorophenylboronic acid (32.24 g), CsF (64 g)and tetrakis(triphenylphosphine)palladium(0) (2 g) in 2:1dimethoxyethane/mehanol (600 mL) were heated to 70° C. for 24 hours. Themixture was concentrated. Ether was added, and the mixture was filteredand concentrated.

EXAMPLE 3D (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To a mixture of LiBH₄ (13 g), EXAMPLE 3C (53.8 g) and ether (400 mL),methanol (25 mL) was added slowly by syringe. The mixture was stirred atroom temperature for 24 hours. The mixture was quenched with 1N HCl withice-cooling. The mixture was diluted with water and extracted by ether(3×100 mL). The extracts were dried, and concentrated. The concentratewas chromatographed on silica gel with 0-30% ethyl acetate/hexanes.

EXAMPLE 3E tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

Mesyl chloride (7.5 mL) was added via syringe to EXAMPLE 3D (29.3 g) andtriethylamine (30 mL) in CH₂Cl₂ (500 mL) at 0° C., and the mixture wasstirred for 1 minute. N-t-butoxycarbonylpiperazine (25 g) was added andthe mixture was stirred at room temperature for 24 hours. The suspensionwas washed with brine, dried, and concentrated. The concentrate waschromatographed on silic gel with 10-20% ethyl acetate/hexanes.

EXAMPLE 3F1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

This EXAMPLE was prepared by substituting EXAMPLE 3E for EXAMPLE 1A inEXAMPLE 1B.

EXAMPLE 3G ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)-2-(2-methyl-1H-indol-5-yloxy)benzoate

EXAMPLE 3F (1008 mg), EXAMPLE 3 A (900 mg), and HK₂PO₄ (550 mg) werestirred in DMSO (7 mL) at 140° C. for 24 hours. The mixture was dilutedwith ethyl acetate, washed three times with water, washed with brine,dried, and concentrated. The concentrate was chromatographed on silicagel wtih 30% ethyl acetate/hexanes.

EXAMPLE 3H4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-((2-methyl)-1H-indol-5-yloxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 3G for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 3I 4-(1-methylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide

This EXAMPLE was prepared by substituting 4-amino-N-methylpiperidine for3-(N-morpholinyl)-1-propylamine in EXAMPLE 4A.

EXAMPLE 3J4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((1-(methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 3H for EXAMPLE 1F andEXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H, ¹H NMR (300 MHz, DMSO-d₆) δ10.98 (s, 1H), 10.50 (br s, 1H), 8.55 (dd, 1H), 8.17 (d, 1H), 7.88 (dd,1H), 7.51 (d, 1H), 7.34 (d, 2H), 7.24 (d, 1H), 7.14 (d, 1H), 7.05 (d,2H), 7.00 (d, 1H), 6.72 (d, 1H), 6.55 (d, 1H), 6.08 (d, 2H), 3.85 (m,1H), 3.45 (m, 4H), 2.98 (br s, 4H), 2.85 (m, 2H), 2.71 (br s, 2H), 2.63(s, 2H), 2.38 (s, 2H), 2.15 (m, 6H), 1.95 (m, 4H), 1.80 (m, 2H), 1.38(m, 2H), 0.92 (s, 6H).

EXAMPLE 44-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 4A 4-(3-morpholinopropylamino)-3-nitrobenzenesulfonamide

4-Fluoro-3-nitrobenzenesulfonamide (550 mg),3-(N-morpholinyl)-1-propylamine (1.00 g), and triethylamine (1 g )werestirred in THF (30 mL) for 24 hours. The mixture was diluted with ethylacetate, washed with NaH₂PO₄ solution and brine, and dried (Na₂SO₄),filtered and concentrated. The product was triturated from ethylacetate.

EXAMPLE 4B4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 4A for EXAMPLE 1F andEXAMPLE 3H for EXAMPLE 2G in EXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ10.98 (m, 2H), 8.80 (dd, 1H), 8.58 (d, 1H), 7.82 (dd, 1H), 7.50 (d, 1H),7.34 (d, 2H), 7.27 (d, 1H), 7.05 (m, 4H), 6.75 (d, 1H), 6.62 (d, 1H),6.10 (d, 1H), 3.60 (m, 4H), 3.45 (m, 2H), 3.01 (br s, 4H), 2.71 (br s,3H), 2.38 (m, 8H), 2.14 (br s, 6H), 1.95 (m, 2H), 1.81 (m, 2H), 1.38 (m,2H), 0.92 (s, 6H).

EXAMPLE 54-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 5A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)benzoate

This EXAMPLE was prepared by substituting 2-chlorophenol for EXAMPLE 1Din EXAMPLE 1E.

EXAMPLE 5B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 5A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 5C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 5B for EXAMPLE 1F isEXAMPLE 1H. The crude product was purified by preparative HPLC using a250×50 mm C18 column and eluing with 20-100% CH₃CN vs. 0.1%trifluoroacetic acid in water, giving the product as a trifluoroacetatesalt. ¹H NMR (300 MHz, DMSO-d₆) δ 11.77 (br s, 1H), 9.58 (v br s, 1H),8.63 (t, 1H), 8.46 (d, 1H), 7.79 (dd, 1H), 7.71 (br s, 1H), 7.52 (m,5H), 7.33 (m, 4H), 7.15 (d, 1H), 7.13 (m, 1H), 6.99 (m, 1H), 6.78 (dd,1H), 6.65 (d, 1H), 6.40 (s, 1H), 4.35 (v br s, 1H), 3.90 (m, 2H),3.80-2.80 (v br m, 7H), 3.36 (m, 4H), 3.27 (m, 2H), 1.90 (m, 1H), 1.63(m, 2H), 1.28 (m, 2H).

EXAMPLE 64-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 6A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)benzoate

This EXAMPLE was prepared by substituting 3-chlorophenol for EXAMPLE 1Din EXAMPLE 1E.

EXAMPLE 6B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 6A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 6C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 6B for EXAMPLE 5B inEXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆) δ 11. 85 (br s, 1H), 9.60 (v br s,1H), 8.63 (t, 1H), 8.43 (d, 1H), 7.72 (dd, 1H), 7.70 (br s, 1H), 7.50(m, 5H), 7.40 (d, 2H), 7.35 (m, 1H), 7.19 (dd, 1H), 7.14 (d, 1H), 6.95(m, 1H), 6.80 (dd, 1H), 6.72 (m, 1H), 6.70 (m, 1H), 6.56 (d, 1H), 4.35(v br s, 1H), 3.90 (m, 2H), 3.80-2.80 (v br m, 7H), 3.36 (m, 4H), 3.27(m, 2H), 1.90 (m, 1H), 1.63 (m, 2H), 1.28 (m, 2H).

EXAMPLE 74-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 7A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophenoxy)benzoate

This EXAMPLE was prepared by substituting 4-chlorophenol for EXAMPLE 1Din EXAMPLE 1E.

EXAMPLE 7B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 7A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 7C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 7B for EXAMPLE 5B inEXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆) δ 11.81 (br s, 1H), 9.58 (v br s,1H), 8.63 (t, 1H), 8.46 (d, 1H), 7.73 (dd, 1H), 7.71 (br s, 1H), 7.50(m, 5H), 7.38 (d, 2H), 7.33 (m, 1H), 7.25 (m, 2H), 7.15 (d, 1H), 6.79(m, 3H), 6.50 (d, 1H), 4.35 (v br s, 1H), 3.90 (m, 2H), 3.80-2.80 (v brm, 7H), 3.36 (m, 4H), 3.27 (m, 2H), 1.90 (m, 1H), 1.63 (m, 2H), 1.28 (m,2H).

EXAMPLE 84-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 8A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophenoxy)benzoate

This EXAMPLE was prepared by substituting 3-nitrophenol for EXAMPLE 1Din EXAMPLE 1E.

EXAMPLE 8B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 8A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 8C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(nitrophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 8B for EXAMPLE 5B inEXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆) δ 11.81 (br s, 1H), 9.59 (v br s,1H), 8.60 (t, 1H), 8.39 (d, 1H), 7.70 (m, 3H), 7.50 (m, 6H), 7.38 (m,4H), 7.23 (m, 1H), 7.10 (d, 1H), 6.85 (dd, 1H), 6.63 (d, 1H), 4.35 (v brs, 1H), 3.90 (m, 2H), 3.80-2.80 (v br m, 7H), 3.36 (m, 4H), 3.27 (m,2H), 1.90 (m, 1H), 1.63 (m, 2H), 1.28 (m, 2H).

EXAMPLE 94-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxymethyl)phenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 9A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-hydroxymethyl)phenoxy)benzoate

This EXAMPLE was prepared by substituting 3-(hydroxymethyl)phenol forEXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 9B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxymethyl)phenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 9 A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 9C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxymethyl)phenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 9B for EXAMPLE 1F andEXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H, except that the purificationwas performed by HPLC according to EXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆)δ 11.63 (br s, 1H), 9.60 (v br s, 2H), 8.70 (t, 1H), 8.50 (d, 1H), 7.80(dd, 1H), 7.67 (br s, 1H), 7.50 (m, 5H), 7.40 (m, 2H), 7.35 (br s, 1H),7.20 (m, 2H), 6.95 (d, 1H), 6.75 (m, 3H), 6.40 (s, 1H), 4.40 (s, 2H),4.35-2.80 (m, 22 H),1.98 (m, 2H).

EXAMPLE 104-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 5B for EXAMPLE 1F andEXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H, except that the purificationwas performed by HPLC according to EXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆)δ 11.77 (br s, 1H), 9.62 (v br s, 2H), 8.70 (t, 1H), 8.50 (d, 1H), 7.82(dd, 1H), 7.71 (br s, 1H), 7.52 (m, 5H), 7.40 (m, 3H), 7.33 (br s, 1H),7.16 (m, 2H), 7.02 (m, 1H), 6.79 (dd, 1H), 6.70 (d, 1H), 6.40 (s, 1H),4.35-2.80 (m, 22 H), 1.98 (m, 2H).

EXAMPLE 114-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 11A 4-(3-(dimethylamino)propylamino)-3-nitrobenzenesulfonamide

This EXAMPLE was prepared by substituting3-(dimethylamino)-1-propylamine for 3-(N-morpholinyl)-1-propylamine inEXAMPLE 4A,

EXAMPLE 11B4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 5B for EXAMPLE 1F andEXAMPLE 11A for EXAMPLE 1G and EXAMPLE 1H, except that the purificationwas performed by HPLC according to EXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆)δ 11.77 (br s, 1H), 9.38 (v br s, 2H), 8.70 (t, 1H), 8.50 (d, 1H), 7.82(dd, 1H), 7.65 (br s, 1H), 7.52 (m, 5H), 7.40 (m, 3H), 7.33 (br s, 1H),7.16 (m, 2H), 7.02 (m, 1H), 6.79 (dd, 1H), 6.70 (d, 1H), 6.40 (s, 1H),4.35-2.80 (m, 12 H), 2.80 (s, 3H), 2.78 (s, 3H), 1.98 (m, 2H).

EXAMPLE 124-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy-N-((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 6B for EXAMPLE 1F andEXAMPLE 4 A for EXAMPLE 1G is EXAMPLE 1H, except that the purificationwas performed by HPLC according to EXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆)δ 11.85 (br s, 1H), 9.63 (v br s, 2H), 8.66 (t, 1H), 8.43 (d, 1H), 7.78(dd, 1H), 7.67 (br s, 1H), 7.50 (m, 5H), 7.40 (d, 2H), 7.35 (m, 1H),7.20 (dd, 1H), 7.14 (d, 1H), 6.95 (m, 1H), 6.80 (dd, 1H), 6.72 (m, 1H),6.70 (m, 1H), 6.53 (s, 1H), 4.35-2.80 (m, 22 H), 1.98 (m, 2H).

EXAMPLE 134-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 7B for EXAMPLE 1F andEXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H, except that the purificationwas performed by HPLC according to EXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆)δ 11.81 (br s, 1H), 9.63 (v br s, 2H), 8.70 (t, 1H), 8.50 (d, 1H), 7.80(dd, 1H), 7.69 (br s, 1H), 7.50 (m, 5H), 7.38 (d, 2H), 7.33 (m, 1H),7.25 (m, 2H), 7.15 (d, 1H), 6.79 (m, 3H), 6.50 (d, 1H), 4.35-2.80 (m, 22H), 1.98 (m, 2H).

EXAMPLE 144-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 6B for EXAMPLE 1F andEXAMPLE 11A for EXAMPLE 1G is EXAMPLE 1H, except that the purificationwas performed by HPLC according to EXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆)δ 11.85 (br s, 1H), 9.63 (v br s, 2H), 8.70 (t, 1H), 8.45 (d, 1H), 7.78(dd, 1H), 7.70 (br s, 1H), 7.50 (m, 5H), 7.40 (d, 2H), 7.35 (m, 1H),7.20 (dd, 1H), 7.14 (d, 1H), 6.95 (m, 1H), 6.80 (dd, 1H), 6.72 (m, 1H),6.70 (m, 1H), 6.56 (s, 1H), 4.35-2.80 (m, 12 H), 2.52 (s, 3H), 2.50 (s,3H), 2.00 (m, 2H).

EXAMPLE 154-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-((4-((3-dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 7B for EXAMPLE 1F andEXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H, except that the purificationwas performed by HPLC according to EXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆)δ 11.81 (br s, 1H), 9.38 (v br s, 1H), 8.68 (t, 1H), 8.50 (d, 1H), 7.80(dd, 1H), 7.69 (br s, 1H), 7.50 (m, 5H), 7.40 (d, 2H), 7.33 (m, 1H),7.25 (m, 2H), 7.15 (d, 1H), 6.80 (m, 3H), 6.46 (s, 1H), 4.35-2.80 (m, 12H), 2.81 (s, 3H), 2.79 (s, 3H), 1.98 (m, 2H).

EXAMPLE 164-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((1-methyl-1H-indol-4-)yl)oxy)benzamideEXAMPLE 16A 1-(triisopropylsilyl)-1H-indol-4-ol

4-Benzyloxyindole (1 g) was treated with 60% oily NaH (135 mg) andtriisopropylsilyl chloride (1 g) in THF, purified by flashchromatography (98/2 ethyl acetate/hexanes), then debenzylated inethanol (35 mL) using Pearlman's catalyst (0.19 g) and a hydrogenballoon.

EXAMPLE 16B methyl2-(1H-indol-4-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 16A for EXAMPLE 1D inEXAMPLE 1E. The crude material from the ether formation was desilylatedusing tetrabutyl ammonium fluoride in THF/water 95/5 for 1 hour prior topurification.

EXAMPLE 16C methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(1-methyl-1H-indol-4-yloxy)benzoate

EXAMPLE 16B (148 mg), 60% oily NaH (9 mg) and methyliodide (57 mg) inTHF (1 mL) were stirred at room temperature overnight. The mixture waschromatographed on silica gel with 20% ethyl acetate in hexanes.

EXAMPLE 16D4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(1-methyl-1H-indol-4-yloxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 16C for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 16E4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((1-methyl-1H-indol-4-)yl)oxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 11A for EXAMPLE 1G andEXAMPLE 16D for EXAMPLE 1E in EXAMPLE 1H, except that the purificationwas performed by HPLC according to EXAMPLE 5C. ¹H NMR (300 MHz, DMSO-d₆)δ 11.58 (br s, 1H), 9.42 (br s, 2H), 8.64 (t, 1H), 8.44 (d, 1H), 7.77(dd, 1H), 7.66 (br s, 1H), 7.50 (m, 5H), 7.37 (d, 2H), 7.30 (m, 1H),7.25 (d, 1H), 7.19 (d, 1H), 7.06 (d, 1H), 7.00 (dd, 1H), 6.75 (dd, 1H),6.40 (d, 1H), 6.38 (s, 1H), 6.23 (d, 1H), 4.35-2.80 (m, 12 H), 3.80 (s,3H), 2.79 (s, (3H), 2.77 (s, 3H), 1.96 (m, 2H).

EXAMPLE 172-(3-(acetylamino)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 17A2-(3-(acetamindophenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This EXAMPLE was prepared by substituting 3-acetamidophenol for EXAMPLE1D in EXAMPLE 1E.

EXAMPLE 17B2-(3-(acetamindophenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 17A for EXAMPLE 1E inEXAMPLE 1F.

EXMAPLE 17C2-(3-(acetylamino)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 17B for EXAMPLE 1F inEXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ 11.48 (s, 1H), 9.89 (s, 1H),8.59 (m, 1H), 8.50 (d, 1H), 7.71 (dd, 1H), 7.47 (m, 6H), 7.36 (m, 2H),7.24 (m, 2H), 7.14 (m, 3H), 6.75 (dd, 1H), 6.30 (dd, 1H), 6.39 (d, 1H),3.86 (dd, 2H), 3.37 (m, 2H), 3.30 (m, 6H), 3.10 (m, 4H), 2.35 (s, 4H),2.00 (s, 3H), 1.89 (m, 1H), 1.63 (dd, 2H), 1.27 (m, 2H).

EXAMPLE 182-(4-aminophenoxy-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 18A methyl2-(4-(tert-butoxycarbonylamino)phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This EXAMPLE was prepared by substitutingN-tert-butoxycarbonyl-4-aminophenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 18B2-(4-(tert-butoxycarbonylamino)phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 18A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 18C tert-butyl4-(5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)phenylcarbamate

This EXAMPLE was prepaid by substituting EXAMPLE 18B for EXAMPLE 1F inEXAMPLE 1H.

EXAMPLE 18D2-(4-aminophenoxy-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepaid by substituting EXAMPLE 18C for EXAMPLE 1A inEXAMPLE 1B. ¹H NMR (300 MHz, DMSO-d₆) δ 11.41 (s, 1H), 9.54 (s, 1H),8.66 (t, 1H), 8.59 (d, 1H), 7.86 (dd, 1H), 7.67 (m, 1H), 7.51 (dd, 5H),7.38 (d, 2H), 7.31 (m, 1H), 7.25 (d, 1H), 6.82 (m, 4H), 6.69 (dd, 1H),6.24 (m, 1H), 4.26 (s, 2H), 3.85 (dd, 2H), 3.35 (m, 4H), 3.26 (td, 4H),3.04 (m, 4H), 2.81 (m, 2H), 1.91 (m, 1H), 1.62 (dd, 2H), 1.26 (m, 2H).

EXAMPLE 192-(3-aminophenoxy-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 19A methyl2-(3-(tert-butoxycarbonylamino)phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This EXAMPLE was prepared by substitutingN-tert-butoxycarbonyl-3-aminophenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 19B2-(3-tert-butoxycarbonylamino)phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 19A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 19C tert-butyl3-(5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)phenylcarbamate

This EXAMPLE was prepared by substituting EXAMPLE 19B for EXAMPLE 1F inEXAMPLE 1H.

EXAMPLE 19D2-(3-aminophenoxy-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 19C for EXAMPLE 1A inEXAMPLE 1B. ¹H NMR (300 MHz, DMSO-d₆) δ 11.39 (s, 1H), 9.50 (s, 1H),8.64 (t, 1H), 8.54 (d, 1H), 7.75 (dd, 2H), 7.51 (d, 5H), 7.38 (m, 2H),7.31 (m, 1H), 7.16 (d, 1H), 6.92 (t, 1H), 6.73 (dd, 1H), 6.38 (d, 1H),6.28 (m, 1H), 6.09 (m, 1H), 6.02 (d, 1H), 5.24 (m, 1H), 4.36 (m, 1H),3.86 (dd, 2H), 3.72 (m, 1H), 3.28 (m, 8H), 3.20 (m, 1H), 3.04 (m, 3H),2.85 (m, 1H), 1.90 (m, 1H), 1.63 (dd, 2H), 1.27 (m, 2H).

EXAMPLE 204-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyphenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 20A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyphenoxy)benzoate

This EXAMPLE was prepared by substituting 3-methoxyphenol for EXAMPLE 1Din EXAMPLE 1E.

EXAMPLE 20B4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyphenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 20A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 20C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyphenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 20B for EXAMPLE 1F inEXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.57 (s, 1H), 8.63 (t, 1H),8.47 (d, 1H), 7.76 (dd, 1H), 7.47 (m, 6H), 7.36 (m, 2H), 7.24 (m, 1H),7.11 (m, 2H), 6.76 (dd, 1H), 6.53 (ddd, 1H), 6.35 (m, 3H), 3.86 (m, 2H),3.66 (s, 3H), 3.32 (m, 6H), 3.17 (m, 4H), 2.36 (m, 4H), 1.92 (m, 1H),1.64 (dd, 2H), 1.27 (m, 2H).

EXAMPLE 214-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-dimethylamino)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 21A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(dimethylamino)phenoxy)benzoate

This EXAMPLE was prepared by substituting 3-(dimethylamino)phenol forEXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 21B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(dimethylamino)phenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 21A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 21C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-dimethylamino)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 21B for EXAMPLE 1F inEXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.36 (s, 1H), 8.63 (t, 1H),8.51 (d, 1H), 7.79 (dd, 1H), 7.46 (m, 6H), 7.36 (m, 2H), 7.24 (m, 1H),7.15 (d, 1H), 7.04 (t, 1H), 6.72 (dd, 1H), 6.39 (dd, 1H), 6.33 (d, 1H),6.24 (t, 1H), 6.10 (dd, 1H), 3.86 (dd, 2H), 3.32 (m, 6H), 3.13 (m, 4H),2.83 (s, 6H), 2.34 (m, 4H), 1.90 (m, 1H), 1.63 (dd, 2H), 1.27 (m, 2H).

EXAMPLE 224-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-cyanophenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 22A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-cyanophenoxy)benzoate

This EXAMPLE was prepared by substituting 3-cyanophenol for EXAMPLE 1Dis EXAMPLE 1E.

EXAMPLE 22B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-cyanophenoxy)benzoicacid

A mixture of EXAMPLE 22A (0.081 g) in pyridine (2 mL) in a 10 mLmicrowave vial equipped with a magnetic stir bar was treated with LiI(0.402 g), flushed with nitrogen and heated in a CEM microwave reactorat 120° C. for 30 minutes. The mixture was concentrated, acidified with1N HCl, extracted with ethyl acetate and dried (MgSO₄), filtered andconcentrated. The concentrate was purified by column chromatography onsilica gel, eluting with a gradient of 0-10% methanol indichloromethane.

EXAMPLE 22C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-cyanophenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 22B for EXAMPLE 1F inEXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.78 (s, 1H), 8.62 (t, 1H),8.41 (d, 1H), 7.72 (dd, 1H), 7.48 (m, 6H), 7.34 (m, 4H), 7.25 (m, 1H),7.08 (m, 3H), 6.82 (dd, 1H), 6.54 (d, 1H), 3.87 (dd, 2H), 3.33 (m, 6H),3.22 (m, 4H), 2.38 (m, 4H), 1.93 (m, 1H), 1.65 (dd, 2H), 1.29 (m, 2H).

EXAMPLE 234-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1,3-benzothiazol-6-yl)oxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 23A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(methylbenzo[d]thiazol-6-yloxy)benzoate

This EXAMPLE was prepared by substituting 2-methylbenzothiazol-6-ol forEXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 23B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(methylbenzo[d]thiazol-6-yloxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 23A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 23C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1,3-benzothiazol-6-yl)oxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 23B for EXAMPLE 1F inEXAMPLE 1H. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.78 (s, 1H), 8.56 (t, 1H),8.40 (d, 1H), 7.71 (d, 2H), 7.64 (dd, 1H), 7.51 (m, 5H), 7.37 (d, 2H),7.32 (m, 1H), 7.28 (d, 1H), 6.98 (dd, 1H), 6.79 (dd, 1H), 6.51 (m, 1H),4.33 (br s, 1H), 3.87 (dd, 2H), 3.69 (br s, 2H), 3.28 (m, 4H), 3.04 (brs, 2H), 2.84 (br s, 1H), 2.74 (s, 3H), 2.49 (m, 4H), 1.90 (br s, 1H),1.63 (dd, 2H), 1.28 (m, 3H).

EXAMPLE 244-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1,3-benzothiazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 24A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(methylbenzo[d]thiazol-5-yloxy)benzoate

This EXAMPLE was prepared by substituting 2-methylbenzothiazol-5-ol forEXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 24B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(methylbenzo[d]thiazol-5-yloxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 24A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 24C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1,3-benzothiazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 24B and EXAMPLE 4A forEXAMPLE 1F and EXAMPLE 1G respectively, in EXAMPLE 1H. ¹H NMR (300 MHz,DMSO-d₆) δ 11.83 (s, 1H), 9.48 (br s, 1H), 8.64 (t, 1H), 8.45 (d, 1H),7.88 (d, 1H), 7.76 (dd, 1H), 7.50 (m, 5H), 7.37 (m, 2H), 7.30 (m, 1H),7.18 (m, 1H), 7.04 (d, 1H), 6.97 (dd, 1H), 6.78 (dd, 1H), 6.48 (br s,1H), 4.35 (br s, 1H), 3.98 (m, 3H), 3.77 (br s, 2H), 3.60 (t, 4H), 3.49(m, 2H), 3.15 (m, 4H), 3.04 (m, 4H), 2.75 (s, 3H), 2.56 (m, 2H), 1.94(m, 2H).

EXAMPLE 254-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-((2-methyl-1,3-benzothiazol-5-yl)oxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 24B andEXAMPLE 11A forEXAMPLE 1F and EXAMPLE 1G respectively, in EXAMPLE 1H. ¹H NMR (300 MHz,DMSO-d₆) δ 11.86 (s, 1H), 9.23 (br s, 1H), 8.63 (t, 1H), 8.46 (d, 1H),7.88 (d, 1H), 7.77 (dd, 2H), 7.51 (m, 6H), 7.39 (m, 3H), 7.32 (br s,1H), 7.19 (m, 1H), 7.04 (d, 1H), 6.98 (dd, 1H), 6.79 (dd, 1H), 6.49 (brs, 1H), 4.37 (br s, 1H), 3.76 (br s, 2H), 3.49 (m, 4H). 3.11 (m, 4H),2.79 (s, 3H), 2.77 (s, 3H), 2.76 (s, 3H), 1.94 (m, 2H).

EXAMPLE 264-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimethylamino)-3-oxopropyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 26A 3-(2-hydroxyphenyl)-N,N-dimethylpropanamide

A solution of chroman-2-one (444 mg) in THF (1 mL) was treated withdimethylamine (7.5 mL) and stirred at room temperature for 5 hours. Thesolution was concentrated. The concentrate was filtered through a smallpad of silica gel.

EXAMPLE 26B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(dimethylamino)-3-oxopropyl)phenoxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 26A for EXAMPLE 1D inEXAMPLE 1E.

EXAMPLE 26C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimethylamino)-3-oxopropyl)phenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 26B for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 26D4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimethylamino)-3-oxopropyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 26C for EXAMPLE 1F inEXAMPLE 1H. ¹H NMR (500 MHz, DMSO-d₆) δ 11.74 (s, 1H), 8.65 (t, 1H),8.44 (d, 1H), 7.73 (dd, 2H), 7.52 (m, 5H), 7.35 (d, 3H), 7.13 (dd, 2H),6.96 (t, 1H), 6.87 (t, 1H), 6.75 (dd, 1H), 6.44 (d, 1H), 6.39 (d, 1H),3.87 (dd, 2H), 3.67 (br, 8H), 3.34 (t, 2H), 3.28 (t, 2H), 3.00 (br, 2H),2.91 (s, 3H), 2.79 (s, 3H), 2.74 (t, 2H), 2.55 (t, 2H), 1.91 (m, 1H),1.64 (d, 2H), 1.29 (m, 2H).

EXAMPLE 274-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimethylamino)-2-oxoethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 27A 2-(2-hydroxyphenyl)-N,N-dimethylacetamide

This EXAMPLE was prepared by substituting benzofuran-2(3H)-one forchroman-2-one in EXAMPLE 26A.

EXAMPLE 27B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimethylamino)-2-oxoethyl)phenoxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 27A for EXAMPLE 1D inEXAMPLE 1E.

EXAMPLE 27C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimethylamino)-2-oxoethyl)phenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 27B for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 27D4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimethylamino)-2-oxoethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 27C for EXAMPLE 1F inEXAMPLE 1H. ¹H NMR (500 MHz, DMSO-d₆) δ 8.64 (t, 1H), 8.52 (d, 1H), 7.82(dd, 1H), 7.70 (s, 1H), 7.52 (dd, 5H), 7.37 (d, 2H), 7.33 (s, 1H), 7.19(m, 2H), 7.14 (t, 1H), 7.03 (t, 1H), 6.70 (m, 2H), 6.23 (s, 1H), 3.86(dd, 2H), 3.64 (s, 2H), 3.40 (br, 12H), 3.25 (t, 2H), 2.92 (s, 3H), 2.72(s, 3H), 1.91 (s, 1H), 1.63 (d, 2H), 1.28 (m, 2H).

EXAMPLE 284-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-dimethylamino)propyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 28A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimethylamino)propyl)phenoxy)benzoate

A solution of EXAMPLE 26B (211 mg) in THF (1.7 mL) at room temperaturewas treated with borane (689 μL) and stirred for 24 hours. The mixturewas quenched with 1N HCl and heated at 50° C. overnight. The solutionwas concentrated. The concentrate was purified by flash chromatography(0-5% 7N NH₃ in 10% methanol/dichloromethane).

EXAMPLE 28B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimethylamino)propyl)phenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 28A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 28C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-dimethylamino)propyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 28B for EXAMPLE 1F inEXAMPLE 1H. ¹H NMR (500 MHz, DMSO-d₆) δ 8.65 (t, 1H), 8.44 (d, 1H), 7.75(dd, 1H), 7.51 (m, 6H), 7.39 (d, 2H), 7.32 (s, 1H), 7.16 (m, 2H), 6.98(m, 1H), 6.90 (t, 1H), 6.76 (d, 1H), 6.48 (d, 1H), 6.37 (s, 1H), 3.87(d, 2H), 3.35 (m, 2H), 3.29 (m, 2H), 3.07 (s, 2H), 2.79 (s, 6H), 2.61(t, 2H), 1.94 (s, 2H), 1.64 (d, 2H), 1.30 (m, 2H).

EXAMPLE 294-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 29A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimethylamino)propyl)phenoxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 27B for EXAMPLE 26B inEXAMPLE 28 A.

EXAMPLE 29B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimethylamino)propyl)phenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 29A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 29C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 29B for EXAMPLE 1F inEXAMPLE 1H. ¹H NMR (500 MHz, DMSO-d₆) δ 8.64 (t, 1H), 8.44 (d, 1H), 7.72(m, 2H), 7.53 (m, 5H), 7.38 (d, 2H), 7.32 (m, 1H), 7.19 (dd, 1H), 7.15(d, 1H), 7.01 (td, 1H), 6.90 (t, 1H), 6.79 (dd, 1H), 6.49 (d, 1H), 6.42(d, 1H), 3.88 (m, 2H), 3.60 (br, 10H), 3.35 (t, 2H), 3.29 (t, 4H), 2.97(m, 2H), 2.81 (m, 6H), 1.92 (s, 1H), 1.65 (m, 2H), 1.30 (m, 2H).

EXAMPLE 302-(5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)-N,N-dimethylbenzamideEXAMPLE 30A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(dimethylcarbamoyl)phenoxy)benzoate

This EXAMPLE was prepared by substituting2-hydroxy-N,N-dimethylbenzamide for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 30B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(dimethylcarbamoyl)phenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 30A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 30C2-(5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)-N,N-dimethylbenzamide

This EXAMPLE was prepared by substituting EXAMPLE 30B for EXAMPLE 1F inEXAMPLE 1H. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (t, 1H), 8.52 (d, 1H), 7.83(dd, 1H), 7.71 (s, 1H), 7.51 (m, 5H), 7.30 (m, 5H), 7.20 (d, 1H), 7.13(t, 1H), 6.82 (d, 1H), 6.74 (m, 1H), 6.24 (d, 1H), 4.30 (s, 1H), 3.80(br, 11H), 3.34 (t, 2H), 3.27 (t, 2H), 2.79 (s, 3H), 2.66 (s, 3H), 1.90(s, 1H), 1.62 (d, 2H), 1.27 (ddd, 2H).

EXAMPLE 314-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 31A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(dimethylamino)methyl)phenoxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 30A for EXAMPLE 26B inEXAMPLE 28A.

EXAMPLE 31B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(dimethylamino)methyl)phenoxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 31A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 31C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 31B for EXAMPLE 1F inEXAMPLE 1H. ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (m, 1H), 8.38 (d, 1H), 7.70(dd, 1H), 7.61 (d, 1H), 7.51 (d, 4H), 7.39 (m, 4H), 7.33 (s, 1H), 7.15(m, 2H), 6.97 (t, 1H), 6.84 (d, 1H), 6.61 (s, 1H), 6.43 (d, 1H), 4.33(s, 2H), 3.88 (d, 2H), 3.55 (br, 10H), 3.35 (m, 2H), 3.29 (m, 2H), 2.78(s, 6H), 1.92 (s, 1H), 1.64 (d, 2H), 1.31 (m, 2H).

EXAMPLE 324-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-morpholin-4-ylphenoxy)benzamideEXAMPLE 32A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(morpholinophenoxy)benzoate

This EXAMPLE was prepared by substituting 3-morpholinophenol for EXAMPLE1D to EXAMPLE 1E.

EXAMPLE 32B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(morpholinophenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 32A for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 32C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-morpholin-4-ylphenoxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 32B for EXAMPLE 1F andEXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz, DMSO-d₆) δ11.61 (br s, 1H), 9.50 (br s, 1H), 8.69 (t, 1H), 8.51 (d, 1H), 7.83 (dd,1H), 7.68 (m, 1H), 7.50 (m, 5H), 7.39 (m, 2H), 7.31 (m, 1H), 7.15 (d,3H), 7.08 (m. 1H), 6.75 (dd, 1H), 6.59 (dd, 1H), 6.40 (m, 2H), 6.23 (m,1H), 3.71 (m, 4H), 3.52 (m, 4H), 3.40 (m, 4H), 3.13 (m, 4H), 3.00 (m,6H), 2.78 (s, 6H), 1.96 (m, 2H).

EXAMPLE 334-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dimethyl-1,3-thiazol-5-yl)phenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 33A methyl2-(3-(benzyloxy)phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This EXAMPLE was prepared by substituting 3-(benzyloxy)phenol forEXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 33B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-hydroxyphenoxy)benzoate

EXAMPLE 33 A (510 mg) in CH₂Cl₂ (5 mL) was cooled to 0° C., treated with1M BBr₃ CH₂Cl₂ (4 mL), and stirred at room temperature for 2 hours. Themixture was quenched with saturated NaHCO₃ solution and extracted withethyl acetate. The extract was washed with water and brine, dried overNa₂SO₄ and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 0-30% ethyl acetate in hexane.

EXAMPLE 33C methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3(trifluoromethylsulfonyloxy)phenoxy)benzoate

EXAMPLE 33B (180 mg) in THF (5 mL) was cooled to −78° C., and 0.5 mL of1M lithium hexamethyldisilazide in THF was added. The mixture wasstirred for 15 minutes then treated with 1,11-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (146mg). The mixture was warmed to room temperature overnight, quenched withsaturated NH₄Cl solution and extracted with ethyl acetate. The extractwas washed with water and brine, dried over Na₂SO₄ and concentrated.

EXAMPLE 33D methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dimethylthiazol-5-yl)phenoxy)benzoate

EXAMPLE 33C (60 mg),2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl)thiazole(36 mg) and dichlorobis(triphenylphosphine) palladium(II) (2 mg) weredissolved in 5 mL of a dimethoxyethane:ethanol:2M Na₂CO₃ solution(7:2:2). The mixture was heated at 130° C. for 15 minutes in a microwavereactor and concentrated. The concentrate was purified by flash columnchromatography with 0-30% ethyl acetate/hexanes.

EXAMPLE 33E methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dimethylthiazol-5-yl)phenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 33D for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 33F4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dimethyl-1,3-thiazol-5-yl)phenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 33E for EXAMPLE 1F andEXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz, DMSO-d₆) δ11.80 (br s, 1H), 9.67 (br s, 1H), 8.63 (t, 1H), 8.47 (d, 1H), 7.78 (dd,1H), 7.68 (m, 1H), 7.52 (m, 5H), 7.35 (m, 4H), 7.10 (d, 1H), 7.05 (d,1H), 6.77 (m, 3H), 6.57 (m, 1H), 3.95 (m, 2H), 3.60 (m, 6H), 3.45 (m,6H), 3.16 (m, 4H), 3.07 (m, 4H), 2.31 (s, 3H)S 2.26 (s, 3H), 1.95 (m,2H).

EXAMPLE 342-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 34A ethyl 2-(2-chlorophenoxy)-4-fluorobenzoate

This EXAMPLE was prepared by substituting 2-chlorophenol2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 34B2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 34A for EXAMPLE 3A isEXAMPLE 3G.

EXAMPLE 34C2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 34B for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 34D2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 34C for EXAMPLE 1F andEXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, pyridine-d₅) δ8.37 (d, 1H), 8.08 (d, 1H), 7.76 (dd, 1H), 7.62 (d, 1H), 7.36 (d, 2H),7.35 (d, 1H), 7.07 (d, 2H), 7.07-7.03 (m, 2H), 6.90 (td, 1H), 6.71 (dd,1H), 6.55 (dd, 1H), 6.26 (d, 1H), 3.81 (m, 1H), 3.21 (m, 2H), 3.08 (m,4H), 2.86 (m, 2H), 2.76 (s, 2H), 2.63 (s, 3H), 2.28-2.04 (m, 8H), 1.97(s, 2H), 1.76 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 354-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(3,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 35A ethyl 2-(3,5-dichlorophenoxy)-4-fluorobenzoate

This EXAMPLE was prepared by substituting 3,5-dichlorophenol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 35B4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3,5-dichlorophenoxy)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 35A for EXAMPLE 3A inEXAMPLE 3G.

EXAMPLE 35C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3,5-dichlorophenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 35B for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 35D4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(3,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 35C for EXAMPLE 1F andEXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz, pyridine-d₅) δ9.14 (d, 1H), 8.53 (m, 1H), 8.32 (m, 1H), 7.95 (d, 1H), 7.46 (d, 2H),7.11 (d, 2H), 6.99 (m, 3H), 6.81 (m, 2H), 3.73 (m, 1H), 3.22 (m, 4H),3.05 (m, 2H), 2.85 (s, 2H), 2.56 (m, 2H), 2.46 (s, 3H), 2.30 (m, 6H),2.14 (m, 2H), 1.95 (m, 4H), 1.42 (m, 2H), 0.97 (s, 6H).

EXAMPLE 362-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 36A ethyl 2-(3-chlorophenoxy)-4-fluorobenzoate

This EXAMPLE was prepared by substituting 2-chlorophenol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 36B ethyl2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 36A for EXAMPLE 3A inEXAMPLE 3G.

EXAMPLE 36C2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 36B for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 36D2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 36C for EXAMPLE 1F andEXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz, pyridine-d₅) δ9.12 (d, 1H), 8.51 (d, 1H), 8.31 (dd, 1H), 7.99 (d, 1H), 7.45 (d, 1H),7.11 (m, 3H), 7.02 (m, 2H), 6.91 (dd, 1H), 6.82 (dd, 1H), 6.68 (d, 2H),4.05 (br s, 1H), 3.55 (br s, 2H), 3.31 (s, 6H), 2.99 (s, 2H), 2.85 (s,3H), 2.51 (br s, 3H), 2.41 (s, 6H), 1.99 (s, 2H), 1.41 (t, 2H), 0.95 (s,6H).

EXAMPLE 374-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 37A 4′-chloro-4-hydroxybiphenyl-2-carbaldhyde

2-bromo-5-hydroxybenzaldehyde (20 g), 4-chlorophenylboronic acid (17.1g) and dichlorobis)triphenylphosphine) palladium(II) (1.75 g) weredissolved in 475 mL of a dimethoxyethane:ethanol:2M Na₂CO₃ solution(7:2:2). The mixture was heated to reflux for 1 hour. The reactionmixture was then diluted with ethyl acetate, washed thoroughly withwater and with brine, dried over MgSO₄, filtered and concentrated. Theresulting solid was slurried in 500 mL of hexane:ether mixture (2:1).The title compound was collected by filtration.

EXAMPLE 37B tert-butyl4-((4′-chloro-4-hydroxybiphenol-2-yl)methyl)piperazine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 37A for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

EXAMPLE 37C tert-butyl(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazine-1-carboxylate

EXAMPLE 37B (2 g), 2-chloro-N,N-dimethylethanamine hydrochloric acidsalt (2.15 g), and cesium carbonate (9.70 g) were combined in 10 mL ofN,N-dimethylformamide. The resulting mixutre was heated to 80° C.overnight. The reaction was cooled to room temperature, diluted withethyl acetate and poured into water. The aqueous layer was xtracted withethyl acetate, and the combined organic layers were washed thoroughlywith water and with brine, dried over MgSO₄, filtered and concentrated.The crude material was slurried in 100 mL of ether and the product wasobtained by filtration.

EXAMPLE 37D 2-(4′-chloro-2-(piperazin-1-ylmethyl)biphenyl-4-yloxy)-N,N-dimethylethanamine

The title compound was prepared by substituting EXAMPLE 37C for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 37E ethyl4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 36A for EXAMPLE3A and EXAMPLE 37D for EXAMPLE 3F in EXAMPLE 3G.

EXAMPLE 37F4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 37E for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 37G4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 37F for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.88 (br s, 1H), 9.52 (br s, 1H), 9.30 (br s,1H), 8.45 (m, 1H), 8.21 (d, 1H), 7.78 (dd, 1H), 7.50 (m, 3H), 7.38 (m,2H), 7.1B(in, 3H), 6.95 (m, 1H), 6.81 (dd, 1H), 6.72 (dd, 1H), 6.6 H(m,1H), 6.53 (m, 1H), 4, 35 (m, 2H), 3.53 fro, 2B), 3.28 fro, 2H), 3.21 (m,4H), 3.08 (m, 2H), 2.88 (s, 6H), 2, 73 (m, 2H), 2.64 (m, 1H), 2.43 (s,3H), 2.27 (m, 4H), 1.83 (m, 2H).

EXAMPLE 382-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 38A methyl 6,6-dimethyl-4-oxotetrahydro-2H-pyran-3-carboxylate

To a suspension of hexane-washed NaH (0.72 g, 60%) in tetrahydrofuran(30 mL) was added a solution of 2,2-dimethyldihydro-2H-pyran-4(3H)-one(2.0 g) in tetrahydrofuran (20 mL). The suspension was stirred at roomtemperature for 30 minutes. Dimethylcarbonate (6.31 mL) was addeddropwise by syringe. The mixture was heated to reflux for 4 hours. Themixture was acidified with 5% aqueous HCl and extracted withdichloromethane (100 mL×3) and washed with water and brine, and driedover Na₂SO₄. After filtration and concentration, the crude product wasloaded on a column and eluted with 10% ethyl acetate in hexane to givethe product

EXAMPLE 38B

methyl6,6-dimethyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydro-2H-pyran-3-carboxylate

To a cooled (0° C.) stirring suspension of NaH (0.983 g 60% in mineraloil, washed with hexane three times) in ether (50 mL) was added EXAMPLE38A (3.2 g). The mixture was stirred at 0° C. for 30 minutes before theaddition of triflic anhydride (4.2 mL). The mixture was then stirred atroom temperature overnight. The mixture wa diluted with ether (200 mL)and washed with 5% HCl, water and brine. After drying over Na₂SO₄,evaporation of solvent gave the crude product which was used withoutfurther purification.

EXAMPLE 38C methyl4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carboxylate

To a solution of EXAMPLE 38B (2.88 g), 4-chlorophenylboronic acid (1.88g) and tetrakis(triphenylphosphine)palladium(0) (0.578 g) in toluene (40mL) and ethanol (10 mL) was added 2N aqueous Na₂CO₃ (10 mL). The mixturewas stirred at reflux overnight. The mixture was diluted with ether (300mL) and washed with water, grine and dried over Na₂SO₄. After filtrationand evaporation of solvent, the residue was loaded on a column andeluted with 3% ethyl acetate in hexane to give the product.

EXAMPLE 38D4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methanol

To a solution of EXAMPLE 38C (1.6 g) in ether (20 mL) was added LiAlH₄(1.2 g). The mixture was stirred at room temperature for 4 hours. Themixxture was acidified carefully with 5% aqueous HCl and extracted withethyl acetate (100 mL×3) and the combined organic layers were washedwith water, brine and dried over Na₂SO₄. After filtration andevaporation of solvent, the crude product was loaded on a column andeluted with 10% ethyl acetate in hexane to give the product.

EXAMPLE 38E4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carbaldehyde

To a solution of oxalyl chloride (1.1 g) in dichloromethane (30 mL) at−78° C. for 30 minutes, and then a solution of EXAMPLE 38D (1.2 g) indichloromethane (10 mL) was added. The mixture was stirred at −78° C.for 2 hours before the addition of triethylamine (10 mL). The mixturewas stirred overnight and the temperature was allowed to rise to roomtemperature. The mixture was diluted with ether (300 mL) and washed withwater, brine and dried over Na₂SO₄. After filtration and evaporation ofsolvent, the crude product was loaded on a column and eluted with 5%ethyl acetate in hexane to give the product.

EXAMPLE 38F methyl 2-(2-chlorophenoxy)-4-(piperazin-1-yl)benzoate

This example was prepared by substituting piperazine for EXAMPLE 3F andEXAMPLE 34A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 38G methyl2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate

To a solution of EXAMPLE 38E (100 mg) and EXAMPLE 38F (177 mg) indichloromethane (10 mL) was added sodium triacetoxyborohydride (154 mg).The mixture was stirred at room temperature overnight. The mixture wasdiluted with ethyl acetate (200 mL) and washed with 2 wt % aqueous NaOH,water and brine. After drying over Na₂SO₄ and filtration, the solventwas evaporated under vacuum and the residue was loaded on a column andeluted with 30% ethyl acetate in hexane to give the product.

EXAMPLE 38H2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoicacid

To a solution of EXAMPLE 38G (254 mg) in tetrahydrofuran (4 mL),methanol (2 mL) and water (2 mL) was added LiOH H₂O (126 mg). Themixture was stirred at room temperature overnight. The mixture was thenneutralized with 5% aqueous HCl and diluted with ethyl acetate (200 mL).After washing with brine, it was dried over Na₂SO₄. Filtration andevaporation of solvent gave the product.

EXAMPLE 38I2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 38H and EXAMPLE 3I, respectively.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.33 (d, 1H), 8.06 (d, 1H),7.71 (dd, 1H), 7.64 (d, 1H), 7.38 (d, 2H), 7.33 (dd, 1H), 7.16 (d, 2H),7.02 (m, 2H), 6.86 (m, 1H), 6.69 (dd, 1H), 6.49 (dd, 1H), 6.25 (d, 1H),4.14 (m, 2H), 3.73 (m, 1H), 3.04 (m, 10H), 2.87 (m, 2H), 2.42 (m, 4H),2.22 (m, 6H), 1.69 (m, 2H), 1.21 (s, 6H).

EXAMPLE 394-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)ethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 39A 2-(3-(benzyloxy)phenoxy)-N,N-dlmethylethanamine

A solution of 3-(benzyloxy)phenol (2.002 g),2-chloro-N,N-dimethylethanamine (1.459 g) in N,N-dimethylformamide (50mL) was treated with cesium carbonate (3.91 g) and stirred at 50° C.overnight. The mixture was diluted with ethyl acetate and 1N aqueousNaOH and the layers were separated. The aqueous layer was extracted withethyl acetate and the combined organic layers were dried over MgSO₄,filtered and concentrated. The residue was purified by flashchromatography (5% 7N NH₃ in methanol-dichloromethane) to give thedesired product.

EXAMPLE 39B 3-(2-(dimethylamino)ethoxy)phenol

EXAMPLE 39A (450 mg) was dissolved in ethyl acetate (10 mL). The flaskwas flushed with nitrogen three times followed by the addition of 10%Pd/C (45 mg). The reaction mixture was kept under 1 atm of hydrogen atroom temperature overnight. The mixture was filtered and concentrated.The residue was filtered through a small pad of silica gel and used inthe next step without further purification.

EXAMPLE 39C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)ethoxy)phenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 39B for EXAMPLE1D in EXAMPLE 1E.

EXAMPLE 39D4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)ethoxy)phenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 39C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 39E4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 39D for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.69 (m,1H), 9.60 (m, 1H), 8.64 (s, 1H), 8.50 (d, 1H), 7.80 (d, 1H), 7.72 (s,1H), 7.52 (d, 5H), 7.38 (d, 2H), 7.33 (s, 1H), 7.19 (m, 2H), 6.78 (d,1H), 6.65 (d, 1H), 6.45 (dd, 3H), 4.24 (s, 2H), 3.86 (d, 2H), 3.67 (s,10H), 3.48 (s, 2H), 3.35 (t, 2H), 3.27 (t, 2H), 2.85 (s, 6H), 1.91 (s,1H), 1.63 (d, 2H), 1.27 (d, 2H).

EXAMPLE 402-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 40A ethyl 2-(4-amino-3-chlorophenoxy)-4-fluorobenzoate

The title compound was prepared by substituting 4-amino-3-chlorophenolfor 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 40B ethyl2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 40A formethyl-2-bromo-4-fluorobenzoate and EXAMPLE 3F for EXAMPLE 1B in EXAMPLE1C.

EXAMPLE 40C2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 40B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 40D2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 40C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 10.70 (br s, 1H), 8.60 (s, 1H), 8.20 (dd, 1H),7.90 (dd, 1H), 7.45 (d, 1H), 7.35 (d, 2H), 7.24 (d, 1H), 7.06 (d, 2H),6.91 (d, 1H), 6.78 (s, 2H), 6.64 (d, 1H), 6.14 (d, 1H), 5.24 (s, 2H),4.03 (m, 1H), 3.52 (m, 2H), 3.10 (m, 6H), 2.80 (m, 4H), 2.73 (s, 3H),2.18 (m, 6H), 1.99 (m, 2H), 1.82 (m, 2H), 1.38 (m, 2H), 0.94 (s, 6H).

EXAMPLE 412-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-isopropylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 41A 4-(1-isopropylpiperidin-4-ylamino)-3-nitrobenzensulfonamide

A suspension of 4-chloro-3-nitrobenzenesulfonamide (1.664 g)triethylamine (2 mL) and 1-isopropylpiperidin-4-amine (1 g) in dioxane(10 mL) was stirred for 16 hours at 90° C. The reaction mixture wascooled to room temperature and the solid material was filtered off. Thesolid material was washed with 20% methanol/dichloromethane, and themixture was dried under vacuum, to provide the product.

EXAMPLE 41B2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-isopropylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE1F and. EXAMPLE 41A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) δ 9.18 (d, 1H), 8.51 (d, 1H), 8.37 (dd, 1H), 8.01 (d, 1H),7.40-7.49 (m, 3H), 7.10 (d, 2H), 7.00-7.06 (m, 2H), 6.94-6.99 (m, 1H),6.86 (dd, 1H), 6.80 (dd, 1H), 6.54 (d, 2H), 3.90-3.99 (m, 1H), 3.41-3.55(m, 3H), 3.10-3.21 (m, 6H), 2.87 (s, 2H), 2.24-2.45 (m, 10H), 1.99 (s,2H), 1.41 (t, 2H), 1.25 (d, 6H), 0.95 (s, 6H).

EXAMPLE 422-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 42A Ethyl 2-(2-bromophenoxy)-4-fluorobenzoate

The title compound was prepared by substituting 2-bromophenol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 42B

Ethyl2-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 42A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 42C2-(2-Bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 42B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 42D2-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 42C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.81 (s, 1H), 9.24-9.76 (m, 2H), 8.48 (d, 1H),8.21 (d, 1H), 7.84 (dd, 1H), 7.50-7.60 (m, 2H), 7.41 (d, 2H), 7.25 (d,1H), 7.18 (t, 1H), 7.11 (d, 2H), 6.95 (t, 1H), 6.80 (dd, 1H), 6.69 (d,1H), 6.39 (s, 1H), 4.03-4.13 (m, 1H), 3.47-3.65 (m, 5H), 3.20-3.40 (m,3H), 3.01-3.19 (m, 4H), 2.70-2.91 (m, 5H), 2.14-2.26 (m, 4H), 2.04 (s,2H), 1.73-1.93 (m, 2H), 1.48 (t, 2H), 0.96 (s, 6H).

EXAMPLE 432-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 43A ethyl2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

The title compound was prepared as described in EXAMPLE 38B by replacingEXAMPLE 38A with ethyl 2-oxocyclohexanecarboxylate.

EXAMPLE 43B ethyl 2-(4-chlorophenyl)cyclohex-1-enecarboxylate

The title compound was prepared as described in EXAMPLE 38C by replacingEXAMPLE 38B with EXAMPLE 43A.

EXAMPLE 43C (2-(4-chlorophenyl)cyclohex-1-enyl)methanol

The title compound was prepared as described in EXAMPLE 38D by replacingEXAMPLE 38C with EXAMPLE 43B.

EXAMPLE 43D (2-(4-chlorophenyl)cyclohex-1-enylcarbaldehyde

The title compound was prepared as described in EXAMPLE 38E by replacingEXAMPLE 38D with EXAMPLE 43C.

EXAMPLE 43E methyl2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLE 38E with EXAMPLE 43D.

EXAMPLE 43F2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 38 H byreplacing EXAMPLE 38G with EXAMPLE 43E.

EXAMPLE 43G2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 43F and EXAMPLE 3I, respectively,¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.36 (d, 1H), 8.07 (d, 1H),7.74 (dd, 1H), 7.62 (d, 1H), 7.35 (d, 2H), 7.09 (d, 2H), 7.04 (d, 1H),6.89 (m, 1H), 6.70 (dd, 1H), 6.54 (dd, 1H), 6.25 (d, 1H), 3.80 (m, 1H),3.11 (m, 8H), 2.77 (m, 4H), 2.59 (m, 4H), 2.15 (m, 8H), 1.70 (m, 8H).

EXAMPLE 444-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indazol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 44A 4-methoxy-3-methyl-1H-indazole

A solution of 1-(2-fluoro-6-methoxyphenyl)ethanone (1 g), hydrazine(1.04 g), and sodium acetate (0.49 g) was stirred for 72 hours intoluene (10 mL). The mixture was concentrated, taken up in DMSO (8 mL),and heated to 135° C. for 24 hours. The mixture was cooled, poured intoethyl acetate (200 mL), and rinsed with 3× water, and brine. The organiclayer was concentrated and chromatographed on silica gel using 10-100%ethyl acetate/hexanes.

EXAMPLE 44B 3-methyl-1H-indazol-4-ol

A 1M solution of BBr₃ (6.57 mL) was added to a solution of EXAMPLE 44A(0.71 g) in dichloromethane (30 mL), and the reaction was stirred for 18hours. The reaction was quenched by the slow addition of methanol, andthe mixture was concentrated and chromatographed on silica gel using 10%methanol/ethyl acetate.

EXAMPLE 44C ethyl 4-fluoro-2-(3-methyl-1H-indazol-4-yloxy)benzoate

The title compound was prepared by substituting EXAMPLE 44B for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 44D ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indazol-4-yl)benzoate

The title compound was prepared by substituting EXAMPLE 44C formethyl-2-bromo-4-fluorobenzoate and EXAMPLE 3F for EXAMPLE 1B in EXAMPLE1C.

EXAMPLE 44E4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indazol-4-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 40B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 44F4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indazol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 44E for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11. 95 (br s, 2H), 8.47 (m, 1H), 8.27 (d, 1H),7.62 (d, 1H), 7.36 (d, 2H), 7.07 (d, 2H), 6.93 (m, 2H), 6.72 (m, 2H),6.36 1H), 5.92 (d, 1H), 3.61 (m, 4H), 3.04 (m, 4H), 2.75 (m, 2H), 2.39(m, 4H), 2.18 (m, 6H), 1.99 (s, 3H), 1.90 (m, 6H), 1.77 (m, 2H), 1.41(m, 2H), 0.94 (s, 6H).

EXAMPLE 454-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 45A Ethyl 2-(2,3-difluorophenoxy)-4-fluorobenzoate

The title compound was prepared by substituting 2,3-difluorophenol2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 45B4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 45A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 45C

This EXAMPLE was prepared by substituting EXAMPLE 45B for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 45D4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) 9.17 (d, 1H), 8.49 (d, 1H), 8.38 (dd, 1H), 7.99 (d, 1H),7.46 (d, 2H), 7.10 (d, 2H), 7.01 (d, 1H), 6.85 (m, 3H), 6.69 (m, 2H),3.70 (m, 1H), 3.21 (m, 4H), 3.05 (m, 2H), 2.84 (s, 2H), 2.57 (m, 2H),2.46 (s, 3H), 2.28 (m, 6H), 2.11 (m, 2H), 1.94 (m, 4H), 1.42 (t, 2H),0.96 (s, 6H).

EXAMPLE 462-(3-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 46A Ethyl 2-(3-bromophenoxy)-4-fluorobenzoate

The title compound was prepared by substituting 3-bromophenol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 46B Ethyl2-(3-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 46A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 46C2-(3-Bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 46B for EXAMPLE1E EXAMPLE 1F.

EXAMPLE 46D2-(3-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 46C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.97 (s, 1H), 9.46 (s, 1H), 9.38 (s, 1H),8.39-8.48 (m, 1H), 8.21 (d, 1H), 7.78 (dd, 1H), 7.53 (d, 1H), 7.41 (d,2H), 7.08-7.24 (m, 5H), 6.75-6.86 (m, 3H), 6.58 (d, 1H), 4.08 (s, 1H),3, 62 (s, 3H), 3.55 (d, 4H), 3.23-3.39 (m, 3H), 3.05-3.20 (m, 4H),2.78-2.91 (m, 5H), 2.70-2.78 (m, 1H), 2.13-2.28 (m, 4H), 2.05 (s, 2H),1.78-1.92 (m, 2H), 1.48 (t, 2H), 0.96 (s, 6H).

EXAMPLE 472-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-ethylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 47A 4-(3-Ethylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting 1-ethylpiperidin-4-aminefor 1-isopropylpiperidin-4-amine in EXAMPLE 41A.

EXAMPLE 47B2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-ethylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE1F and EXAMPLE 47A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) δ 9.18 (d, 1H), 8.50 (d, 1H), 8.36 (dd, 1H), 8.01 (d, 1H),7.39-7.47 (m, 3H), 7.10 (d, 5H), 7.03-7.06 (m, 2H), 7.02 (dd, 1H), 6.96(td, 2H), 6.85 (dd, 1H), 6.80 (dd, 1H), 6.54 (d, 1H), 3.93-4.00 (m, 1H),3.55 (s, 2H), 3.13-3.21 (m, 5H), 3.10 (q, 2H), 2.90 (s, 2H), 2.28-2.37(m, 8H), 2.22-2.28 (m, 2H), 1.98 (s, 2H), 1.40 (t, 2H), 1.26 (t, 3H),0.95 (s, 6H).

EXAMPLE 482-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1,2,2,6,6-pentamethylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamideEXAMPLE 48A4-(1,2,2,6,6-Pentamethylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting1,2,2,6,6-penamethylpiperidin-4-ylamine for 1-isopropylpiperidin-4-aminein EXAMPLE 41A.

EXAMPLE 48B2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1,2,2,6,6-pentamethylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE1F and EXAMPLE 48A for EXAMPLE 1G is EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) δ 9.19 (d, 1H), 8.45 (d, 1H), 8.37 (dd, 1H), 8.01 (d, 1H),7.45 (d, 3H), 7.09 (d, 2H), 7.06 (s, 1H), 7.02-7.05(m, 2H), 6.99 (td,1H), 6.86 (dd, 2H), 6.80 (dd, 1H), 6.53 (d, 1H), 4.16-4.25 (m, 1H),3.16-3.23 (m, 4H), 2.90 (s, 2H), 2.82 (s, 3H), 2.45-2.54 (m, 2H), 2.31(d, 6H), 2.17 (dd, 2H), 1.98 (s, 2H), 1.55 (s, 6H), 1.46 (s, 6H), 1.40(t, 2H), 0.95 (s, 6H).

EXAMPLE 494-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamideEXAMPLE 49A tert-butyl 1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylcarbamate

A mixture of tert-butyl piperidin-4-ylcarbamate (45 g) anddihydro-2H-pyran-4(3H)-one (24.74 g) in dichloromethane (1000 mL) wawstreated with sodium triacetoxyborohydride (61.9 g), stirred at roomtemperature for 16 hours, washed with 1M sodium hydroxide and dried withanhydrous sodium sulfate, filtered and concentrated. The concentrate wasflash column chromatographed on silica gel with 10-20%methanol/dichloromethane.

EXAMPLE 49B 1-(tetrahydro-2H-pyran-4-yl)piperidin-4-aminedihydrochloride salt

A solution of EXAMPLE 49A (52.57 g) in dichloromethane (900 mL) wastreated with 4M aqueous HCl (462 mL), mixed vigorously at roomtemperature 16 hours and concentrated.

EXAMPLE 49C3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)benzenesulfonamide

A mixture of EXAMPLE 49B (22.12 g), water (43 mL), and triethylamine(43.6 mL) in 1,4-dioxane (300 mL) was stirred at room temperature untilEXAMPLE 49B completely dissolved. The solution was then treated with4-chloro-3-nitrobenzenesulfonamide (20.3 g), heated at 90° C. for 16hours, cooled and concentrated. 10% Methanol in dichloromethane wasadded, and the solution was stirred vigorously at room temperature untila fine suspension existed and then the mixture was filtered.

EXAMPLE 49D4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) δ 9.18 (d, 1H), 8.53 (d, 1H), 8.40 (dd, 1H), 7.99 (d, 1H),7.45 (d, 2H), 7.10 (d, 2H), 7.03 (d, 1H), 6.85 (m, 3H), 6.69 (m, 2H),4.02 (m, 2H), 3.72 (m, 1H), 3.31 (t, 2H), 3.21 (m, 4H), 3.11 (m, 2H),2.83 (m, 3H), 2.66 (m, 2H), 2.30 (m, 6H), 2.16 (m, 2H), 1.93 (m, 4H),1.74 (m, 4H), 1.41 (t, 2H), 0.96 (s, 6H).

EXAMPLE 504-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((7-fluoro-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 50A ((3-fluoro-4-nitrophenoxy)methylene)dibenzene

Bromodiphenylmethane (3.5 g) and 3-fluoro-4-nitrophenol were dissolvedin N,N-dimethylformamide (30 mL), and then K₂CO₃ (4.2 g) was added andthe reaction stirred at room temperature for 60 hours. The reaciton waspartitioned between water and ethyl acetate. The organic layer waswashed with 2M aqueous Na₂CO₃ and brine, then dried over Na₂SO₄. Afterfiltration and concentration, the crude material was purified by columnchromatography using 1.5-2.0% ethyl acetate in hexanes.

EXAMPLE 50B 5-(benzyhydryloxy)-7-fluoro-1H-indole

EXAMPLE 50A (2.0 g) was dissolved in tetrahydrofuran (60 mL), then thatsolution was cooled to −40° C. Vinylmagnesium bromide, 1.0M intetrahydrofuran, (21 mL) was then added dropwise, keeping thetemperature below −30° C. The reaction was stirred at −40° C. for 90minutes, and was partitioned between saturated NH₄Cl and ethyl acetate.The organic layer was washed with brine and dried over Na₂SO₄. Afterfiltration and concentration, the crude material was purified by columnchromatography using 2.5-3.0% ethyl acetate in hexanes.

EXAMPLE 50C 7-fluoro-1H-indol-5-ol

EXAMPLE 50B (240 mg) was dissolved in ethyl acetate (1 mL) and methanol(9 mL), then palladium hydroxide on carbon (35 mg) was added and thereaciton stirred at room temperature under a hydrogen balloon for 90minutes. The reaction was filtered through celite and concentrated togive the crude product which was carried on in the next step withoutfurther purificaction.

EXAMPLE 50D ethyl 4-fluoro-2-(7-fluoro-1H-indol-5-yloxy)benzoate

The title compound was prepared by substituting EXAMPLE 50C for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 50E ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(7-fluoro-1H-indol-5-yloxy)benzoate

The title compound was prepared by substituting EXAMPLE 50D for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 50F4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-((7-fluoro-1H-indol-5-yloxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 50E for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 50G4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((7-fluoro-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamidebis(2,2,2-trifluoroacetate)

EXAMPLE 50F (35 mg), EXAMPLE 3I (17 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (21 mg),and 4-dimethylaminopyridine (14 mg) were stirred in CH₂Cl₂ (1.5 mL)overnight. The reaction was concentrated and the crude material waspurified by preparative HPLC using 250×50 mm C18 column and eluting with20-100% CH₃CN vs 0.1% trifluoroacetic acid in water, giving the productas a trifluoroacetate salt. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.62 (br s, 1H), 9.65, 9.45 (both v br s, total 2H), 8.55 (d, 1H), 8.17(br d, 1H), 7.84 (dd, 1H), 7.50 (d, 1H), 7.43 (t, 1H), 7.39 (d, 2H),7.20 (d, 1H), 7.08 (d, 2H), 6.90 (d, 1H), 6.66 (m, 2H), 6.44 (m, 1H),6.28 (d, 1H), 4.02, 3.82 (both br s, total 2H), 3.60 (v br m, 4H), 3.05(v br m, 5H), 2.85, 2.80 (br m, br s, total 5H), 2.20 (br m, 5H), 2.00(br s, 3H), 1.80 (v br m, 2H) 1.44 (br t, 2H), 0.95 (s, 6H).

EXAMPLE 514-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) δ 9.21 (d, 1H), 9.00 (m, 1H), 8.36 (dd, 1H), 7.97 (d, 1H),7.45 (d, 2H), 7.10 (d, 2H), 6.97 (d, 1H), 6.85 (d, 3H), 6.69 (d, 2H),3.82 (m, 4H), 3.38 (q, 2H), 3.21 (m, 4H), 2.86 (s, 2H), 2.45 (m, 6H),2.28 (m, 6H), 1.99 (s, 2H), 1.80 (m, 2H), 1.41 (t, 2H), 0.96 (s, 6H).

EXAMPLE 522-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 40C for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H.¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.10 (br s, 1H), 8.80 (t, 1H), 8.56 (s, 1H),7.82 (dd, 1H), 7.45 (d, 1H), 7.35 (d, 2H), 7.17 (d, 1H), 7.06 (d, 2H),6.89 (d, 1H), 6.77 (s, 2H), 6.63 (d, 1H), 6.14 (d, 1H), 5.20 (br s, 2H),3.61 (m, 4H), 3.46 (m, 214), 3.07 (m, 4H), 2.75 (m, 2H), 2.44 (m, 6H),2.20 (m, 6H), 1.97 (m, 2H), 1.81 (m, 2H), 1.40 (m, 2H), 0.94 (s, 6H).

EXAMPLES 53

2-(3-chlorophenoxy)-4-(4-((4′-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 53A methyl 5-formyl-2-(trifluoromethylsulfonyloxy)benzoate

Triflic anhydride (7.74 mL) was added to methyl5-formyl-2-hydroxybenzoate (7.5 g) in 150 mL CH₂Cl₂ at 0° C., and thereaction mixture was stirred and allowed to warm to room temperatureover 3 hours. The reaction mixture was diluted with CH₂Cl₂ (150 mL),washed 3× with brine, dried over Na₂SO₄, filtered, and concentrated. Theproduct was used without further purification.

EXAMPLES 53B

methyl 4′-chloro-4-formylbiphenyl-2-carboxylate

EXAMPLE 53A (14.5 g), 4-chlorophenylboronic acid (6.88 g) CsF (12.2 g),and tetrakis(triphenylphosphine)palladium(0) 70° C. for 24 hours. Thereaction mixture was cooled, filtered, and concentrated. The crudeproduct was taken up in ethyl acetate (250 mL), washed with 3×1 Maqueous NaOH, and brine, concentrated, and chromatographed on silica gelwith 10% ethyl acetate/hexanes.

EXAMPLE 53C

methyl 4 ′-chloro-4-(2-oxocthyl)biphcnyl-2-carboxylatc

To a solution of (methoxymethyl)diphenylphosphine oxide (1.62 g) in 40mL tetrahydrofuran at −78° C., was added lithium diisopropylamide (2M,3.3 mL), and after stirring 3 minutes, EXAMPLE 53B (1.57 g) was added,and the solution was warmed to room temperature. NaH (230 mg), and 40 mLN,N-dimethylformamide were added, and the mixture was heated to 60° C.for 1 hour. The reaction mixture was cooled and poured into saturatedaqueous NaH₂PO₄ solution. The resulting solution was extracted twicewith ether, and the combined extracts were washed twice with water, andbrine, and concentrated. The crude mixutre of enol ethers was taken upin 1M aqueous HCl (50 mL) and dioxane (50 mL), and stirred at 60° C. for3 hours. The reaction was cooled and poured into NaHCO₃ solution. Theresulting solution was extracted twice with ether, and the combinedextracts were washed with water, and brine, and concentrated. Theproduct was used without further purification.

EXAMPLE 53D methyl4′-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-carboxylate

The title compound was prepared by substituting EXAMPLE 53C for4′-chlorobiphenyl-2-carboxaldehyde and pyrrolidine for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 53E(4′-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-yl)methanol

Diisobutylaluminum hydride (1M in hexanes, 7.8 mL) was added to asolution of EXAMPLE 53D (0.89 g) in dichloromethane (30 mL) at 0° C.,and the reaction was stirred for 20 minutes. The reaction was quenchedby the slow addition of methanol, and then poured into 1M aqueous NaOH(50 mL). The mixture was extracted twice with ethyl acetate, andextracts were combined, washed with brine, dried over Na₂SO₄, filtered,and concentrated.

EXAMPLE 53F4′-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyhl-2-carbaldehyde

EXAMPLE 53E (0.85 g) and Dess-Martin periodinane (1.26 g) were stirredin dichloromethane (40 mL) for 90 minutes. The reaction was quenchedwith methanol (5 mL), concentrated, and chromatographed on silica gelwith 10-50% ethyl acetate hexanes.

EXAMPLE 53G tert-butyl4-(3-(3-chlorophenoxy)-4-(ethoxycarbonyl)phenyl)piperazine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 36A for methyl2-bromo-4-fluorobenzoate and tert-butyl piperazine-1-carboxylate forEXAMPLE 1B in EXAMPLE 1C.

EXAMPLE 53H ethyl 2-(3-chlorophenoxy)-4-(piperazine-1-yl)benzoate

The title compound was prepared by substituting EXAMPLES 3G for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 53I ethyl4-(4-((4′-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 53F for4′-chlorobipheny-2-carboxaldehyde and EXAMPLE 53H for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 53J4-(4-((4′-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 53I for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 53K2-(3-chlorophenoxy)-4-(4-((4′-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 53J for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.80 (br s,1H), 8.66 (t, 1H), 8.45 (s, 1H), 8.00 (m, 1H), 7.72 (dd, 1H), 7.52 (d,2H), 7.35 (m, 4H), 7.16 (m, 2H), 6.94 (d, 1H), 6.80 (d, 1H), 6.66 (d,2H), 6.55 (m, 1H), 4.32 (m, 1H), 3.85 (m, 2H), 3.56 (m, 2H), 3.33 (m,8H), 3.07 (m, 6H), 2.85 (m, 2H), 2.43 (m, 2H), 2.02 (m, 2H), 1.91 (m,4H), 1.63 (m, 2H), 1.27 (m, 2H).

EXAMPLE 544-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylphenyl-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 54A Ethyl 2-(2,3-dichlorophenoxy)-4-fluorobenzoate

The title compound was prepared by substituting 2,3-dichlorophenol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 54B Ethyl2-(2,3-dichlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 54A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 54C2-(2,3-dichlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 54B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 54D4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylphenyl-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 54C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1 H. ¹H NMR (500 MHz,pyridine-d₅) δ 9.16 (d, IB), 8.50 (d, 1H), 8.33 (dd, 1H), 7.99 (d, 1H),7.45 (d, 2H), 7.11 (t, 3H), 7.04 (d, 1H), 6.95 (t, 1H), 6.84 (dd, 1 H),6.74 (d, 1H), 6.68 (d, 1H), 3.90-3.98 (m, 1H), 3.51 (d, 2H), 3.20-3.27(m, 4H), 3.15 (t, 2H), 2.90 (s, 2H), 2.80 (s, 3H), 2.33 (d, 9 H),2.17-2.26 (m, 2H), 1.99 (s, 2H), 1.41 (t, 2H), 0.96 (s, 6H).

EXAMPLE 554-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(3-methyl-1H-indazol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 44E for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.95 (br s, 2H), 8.30 (d, 1H), 8.02 (d, 1H),7.61 (d, 1H), 7.36 (d, 2H), 7.07 (d, 2H), 6.94 (m, 2H), 6.69 (m, 2H),6.36 (s, 1H), 5.92 (d, 1H), 3.27 (m, 4H), 3.04 (m, 7H), 2.75 (m, 4H),2.49 (m, 4H), 2.22 (m, 8H), 1.99 (s, 3H), 1.77 (m, 2H), 1.39 (m, 2H),0.94 (s, 6H).

EXAMPLE 562-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 56A

(Z)-methyl 2-(trifluoromethylsulfonyloxy)cyclohept-1-enecarboxylate

The title compound was prepared es described in EXAMPLE 38B by replacingEXAMPLE 38A with methyl 2-oxocycloheptanecarboxylate.

EXAMPLE 56B (Z)-methyl 2-(4-chlorophenyl)cyclohept-1-enecarboxylate

The title compound was prepared as described in EXAMPLE 38C by replacingEXAMPLE 38B with EXAMPLE 56A.

EXAMPLE 56C (Z)-(2-(4-chlorophenyl)cyclohept-1-enyl)methanol

The title compound was prepared as described in EXAMPLE 38D by replacingEXAMPLE 38C with EXAMPLE 56B.

EXAMPLE 56D (Z)-2-(4-chlorophenyl)cyclohept-1-enecarbaldehyde

The title compound was prepared as described in EXAMPLE 38E by replacingEXAMPLE 38D with EXAMPLE 56C.

EXAMPLE 56E (Z)-methyl2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLE 38E with EXAMPLE 56D.

EXAMPLE 56F(Z)-2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 38H by replacingEXAMPLE 38G with EXAMPLE 56E.

EXAMPLE 56G2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 56F and EXAMPLE 3I, respectively,¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.35 (d, 1H), 8.06 (d, 1H),7.73 (dd, 1H), 7.63 (d, 1H), 7.35 (d, 2H), 7.04 (m, 4H), 6.88 (m, 1H),6.69 (dd, 1H), 6.52 (dd, 1H), 6.25 (d, 1H), 3.78 (m, 1H), 3.06 (m, 6H),2.70 (m, 4H), 2.38 (m, 4H), 2.26 (m, 5H), 2.07 (m, 4H), 1.73 (m, 5 H),1.52 (m, 5H).

EXAMPLE 574-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(3-(trifluoromethyl)phenoxy)benzamideEXAMPLE 57A Ethyl 4-fluoro-2-(3-(trifluoromethyl)phenoxy)benzoate

The title compound was prepared by substituting3-(trifluoromethyl)phenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 57B Ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-(trifluoromethyl)phenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 57A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 57C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)-2-(3-(trifluoromethyl)phenoxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 57B for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 57D4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(3-(trifluoromethyl)phenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 57C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.32 (d, 1H), 8.04 (m, 1H), 7.66 (m, 2H), 7.35(m, 3H), 7.16 (d, 1H), 7.06 (d, 2H), 6.95 (m, 3H), 6.73 (dd, 1H), 6.42(d, 1H), 3.80 (m, 1H), 3.11 (m, 4H), 2.83 (m, 4H), 2.63 (m, 3H), 2.21(m, 6H), 2.08 (m, 2H), 1.97 (m, 5H), 1.76 (m, 2H), 1.41 (t, 2H), 0.95(s, 6H).

EXAMPLE 584-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)benzamideEXAMPLE 58A methyl 4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-oxo-1,2,3,4-tetrahydroquinolin-5-yloxy)benzoate

The title compound was prepared by substituting3,4-dihydro-5-hydroxy-1H-quinolin-2-one for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 58B 4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-oxo-1,2,3,4-tetrahydroquinolin-5-yloxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 58A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 58C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)benzamide

The title compound was prepared by substituting EXAMPLE 58B for EXAMPLE1F and EXAMPLE 11A for EXAMPLE 1G is EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 10.08 g (s, 1H), 8.64 (t, 1H),8.48 (d, 1H), 7.81 (dd, 1H), 7.50 (m, 6H), 7.39 (m, 2H), 7.29 (m, 1H),7.14 (d, 1H), 6.93 (t, 1H), 6.75 (dd, 1H), 6.51 (d, 1H), 6.39 (m, 1H),6.13 (d, 1H), 4.36 (m, 1H), 3.72 (m, 1H), 3.40 (m, 6H), 3.13 (m, 4H),2.80 (m, 4H), 2.78 (d, 6H), 2.40 (t, 2H), 1.96 (m, 2H).

EXAMPLE 592-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE1F and EXAMPLE 131D for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 7.99 (d, 1H), 7.88 (m, 1H), 7.62 (d, 1H), 7.38(m, 3H).7.06 (d, 3H)S 7.01 (d, 1H), 6.93 (t, 1H), 6.69 (m, 1H), 6.56 (d,1H), 6.50 (s, 1H), 6.24 (d, 1H), 3.25 (m, 10H), 3.07 (s, 2H), 3.07 (s,3H), 2.77 (d, 3H), 2.20 (d, 5H), 2.04 (s, 2H), 1.96 (d, 2H), 1.63 (s,2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 604-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 60A Ethyl 2-(2,5-dichlorophenoxy)-4-fluorobenzoate

The title compound was prepared by substituting 2,5-dichlorophenol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 60B Ethyl 2-(2,5-dichlorophenoxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared by substituting piperazine for EXAMPLE3F and EXAMPLE 60A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 60C 2-chloro-4,4-dimethylcyclohex-1-enecarbaldehyde

Into a 250 mL round-bottomed flask was added N,N-dimethylformamide (3.5mL) in dichloromethane (30 mL) to give a colorless solution. The mixturewas cooled to −10° C., and phosphoryl trichloride (4 mL) was addeddropewise. The solution was warmed up to room temperature, and3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture washeated tyo reflux for overnight. The reaction mixture was quenched by 0°C. solution of sodium acetate (25 g in 50 mL water). TThe aqueous layerwas extracted with ether (3×200 mL). The organic layer's were combined,dried over Na₂SO₄, filtered, and dried under vacuum.

EXAMPLE 60D 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde

Into a 1 L round-bottomed flask was added EXAMPLE 60C (6.8 g),4-chlorophenylboronic acid (6.5 g) and palladium(II) acetate (0.2 g) inwater (100 mL) to give a suspension. Potassium carbonate (15 g) andtetrabutylammonium bromide (10 g) were added. After degassing bysubjecting to vacuum and nitrogen, the mixture was stirred at 45° C. for4 hours. After filtering through silica gel, ether (4×200 mL) was usedto extract the product. The combined organic layers were dried overNa₂SO₄ and filtered. The filtrate was concentrated and purified by flashchromatography on silica with 0 to 10% ethyl acetate in hexanes toprovide the title compound.

EXAMPLE 60E4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-((2,5dichlorophenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 60D for4′chlorobiphenyl-2-carboxaldehye and EXAMPLE 60B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 60F

4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-((2,5dichlorophenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 60E for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 60G4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((2,5dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 60F for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 12.01 (br.s, 1H), 9.92 (br.s, 1H), 9.68 (br.s,1H), 8.43 (m, 1H), 8.19 (d, 1H), 7.80 (dd, 1H), 7.55 (d, 1H), 7.39 (m,3H), 7.23 (d, 1H), 7.11 (d, 2H), 6.97 (dd, 1H), 6.85 (dd, 1H), 6.55 (m,2H), 3.58 (m, 5H), 3.25 (m, 6H), 2.83 (m, 4H), 2.21 (m, 4H), 2.05 (s,2H), 1.87 (m, 2H), 1.48 (t, 2H), 0.96 (s, 6H).

EXAMPLE 612-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 61A Ethyl 2-(2-chloro-4-fluorophenoxy)-4-fluorobenzoate

The title compound was prepared by substituting 2-chloro-4-fluorophenolfor 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 61B Ethyl2-(2-chloro-4-fluorophenoxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared by substituting piperazine for EXAMPLE3F and EXAMPLE 61A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 61C Ethyl2-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 60D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 61B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 61D2-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 61C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 61E2-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 61D for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.40 (m, 1H), 8.08 (m, 1H), 7.78 (dd, 1H), 7.59(d, 1H), 7.33 (m, 3H), 7.07 (m, 3H), 6.92 (m, 1H), 6.69 (dd, 1H), 6.59(m, 1H), 6.25 (d, 1H), 3.84 (m, 1H), 3.08 (m, 4H), 2.77 (m, 8H), 2.16(m, 8 H), 1.97 (s, 2H), 1.75 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 622-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 62A methyl 4,4-dimethyl-2-oxocyclopentanecarboxylate

This compound was prepared according to WO 2006/035061 (page 53).

EXAMPLE 62B methyl4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclopent-2-enecarboxylate

The title compound was prepared as described in EXAMPLE 38B by replacingEXAMPLE 38A with EXAMPLE 62A.

EXAMPLE 62C ethyl2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enecarboxylate

The title compound was prepared as described in EXAMPLE 38C by replacingEXAMPLE 38B with EXAMPLE 62B.

EXAMPLE 62D (2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enyl)methanol

The title compound was prepared as described in EXAMPLE 38D by replacingEXAMPLE 38C with EXAMPLE 62C.

EXAMPLE 62E 2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enecarbaldehyde

The title compound was prepared as described in EXAMPLE 38E by replacingEXAMPLE 38D with EXAMPLE 62D.

EXAMPLE 62F methyl2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLE 38E with EXAMPLE 62E.

EXAMPLE 62G2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 38H by replacingEXAMPLE 38G with EXAMPLE 62F.

EXAMPLE 62H2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 62G and EXAMPLE 3I, respectively.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.35 (d, 1H), 8.06 (d, 1H),7.73 (dd, 1H), 7.64 (d, 1H), 7.33 (m, 5H), 7.04 (m, 2H), 6.88 (m, 1H),6.72 (dd, 1H), 6.52 (dd, 1H), 6.28 (d, 1H), 3.78 (d, 1H), 3.07 (d, 4H),2.71 (m, 6H), 2.33 (m, 8H), 2.06 (m, 4H), 1.74 (m, 4H), 1.10 (m, 6H).

EXAMPLE 634-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 63A ethyl 4-fluoro-2-(3-methyl-1H-indol-4-yloxy)benzoate

The title compound was prepared by substituting 3-methyl-4-indolol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 63B ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indol-4-yloxy)benzoate

The title compound was prepared by substituting EXAMPLE 63A formethyl-2-bromo-4-fluorobenzoate and EXAMPLE 3E for EXAMPLE 1B in EXAMPLE1C.

EXAMPLE 63C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indol-4-yloxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 63B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 63D4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 63C for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 10.92 (br s, 2H), 8.77 (m, 1H), 8.57 (d, 1H),7.82 (dd, 1H), 7.55 (d, 1H), 7.33 (d, 2H), 7.15 (m, 2H), 7.03 (d, 2H),6.99 (m, 2H), 6.67 (d, 1H), 6.45 (d, 1H), 6.12 (d, 1H), 3.68 (m, 4H),3.47 (m, 2H), 3.02 (m, 6H), 2.73 (m, 4H), 2.43 (m, 2H), 2.14 (m, 8H),1.99 (s, 3H), 1.91 (m, 2H), 1.38 (m, 2H), 0.92 (s, 6H).

EXAMPLE 644-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2-chloro-3-(trifluoromethyl)phenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 64A

Ethyl 2-(2-chloro-3-(trifluoromethyl)phenoxy)-4-fluorobenzoate. Thetitle compound was prepared by substituting2-chloro-3-(trifluoromethyl)phenol for 2-methyl-5-indolol EXAMPLE 3A.

EXAMPLE 64B Ethyl2-(2-chloro-3-(trifluoromethyl)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 64A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 64C2-(2-chloro-3-(trifluoromethyl)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 64B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 64D4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2-chloro-3-(trifluoromethyl)phenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 64C for EXAMPLE1E and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 12.02 (s, 1H), 9.76 (s, 1H), 9.52 (s, 1H), 8.42(m, 1H), 8.17 (d, 1H), 7.82 (dd, 1H), 7.58 (d, 1H), 7.41 (m, 3H), 7.27(m, 2H), 7.11 (d, 2H), 6.93 (d, 1H), 6.84 (dd, 1H), 6.57(d, 1H), 3.15(m, 6H), 2.83 (m, 8H), 2.11 (m, 8H), 1.83 (m, 2H), 1.47 (t, 2H), 0.96(s, 6H).

EXAMPLE 652-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopropylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamideEXAMPLE 65A4-(1-cyclopropylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide

To a solution of 4-fluoro-3-nitrobenzenesulonamide (1.26 g) and1-cyclopropylpiperidin-4-amine (0.802 g) in tetrahydrofuran (20 mL) wasadded N,N-diisopropylethylamine (2.22 g) and 4-dimethylaminopyridine (35mg). The mixture was stirred at reflux overnight. The mixture wasdiluted with ethyl acetate (200 mL) and washed with aqueous NaHCO₃,water, and brine and dried over Na₂SO₄. After filtration andconcentration, the residue was dissolved in dichloromethane and loadedon a column and eluted with dichloromethane (500 mL), 5% 7N NH₃ in 10%methanol in dichloromethane (1.5 L) to give the product.

EXAMPLE 65B2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopropylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 34C and EXAMPLE 65A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.46 (dd, 1H),8.22 (t, 1H), 7.81 (m, 2H), 7.53 (d, 1H), 7.37 (m, 4H), 7.14 (m, 1H),7.07 (m, 1H), 6.99 (m, 1H), 6.72 (m, 1H), 6.29 (d, 1H), 3.75 (m, 1H),3.13 (s, 3H), 2.93 (d, 3H), 2.78 (s, 1H), 2.20 (m, 5H), 1.97 (m, 5H),1.59 (m, 5H), 0.94 (s, 6H), 0.42 (m, 5H).

EXAMPLE 664-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 63C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 10.86 (br s, 2B), 8.51 (br s, 1H), 8.15 (d, 1H),7.82 (dd, 1H), 7.55 (d, 1H), 7.33 (d, 2H), 7.15 (m, 2H), 7.03 (d, 2H),6.94 (m, 2H), 6.62 (d, 1H), 6.38 (d, 1H), 6.12 (d, 1H), 3.82 (m, 1H),3.09 (m, 2H), 2.98 (m, 6H), 2.88 (m, 2H), 2.71 (m, 3H), 2.66 (m, 2H),2.11 (m, 8H), 1.99 (s, 3H), 1.82 (m, 2H), 1.38 (m, 2H), 0.92 (s, 6H).

EXAMPLE 674-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 60D for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.71 (m, 1H), 8.43 (d, 1H), 7.75 (dd, 1H), 7.54(d, 1H), 7.36 (m, 3H), 7.07 (m, 3H), 6.94 (dd, 1H), 6.79 (dd, 1H), 6.46(dd, 2H), 3.67 (m, 4H), 3.48 (q, 2H), 3.20 (m, 4H), 2.83 (s, 2H), 2.65(m, 6H), 2.24 (m, 6H), 1.98 (s, 2H), 1.88 (m, 2H), 1.42 (t, 2H), 0.95(s, 6H).

EXAMPLE 684-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 16D for EXAMPLE50F and EXAMPLE 4A for EXAMPLE 3I in EXAMPLE 50G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.58 (br s, 1H), 9.78 (br s, 1H), 8.67 (t, 1H),8.44 (d, 1H), 7.77 (dd, 1H), 7.66 (br s, 1H), 7.50 (m, 5H), 7.37 (d,2H), 7.30 (m, 1H), 7.25 (d, 1H), 7.19 (d, 1H), 7.06 (d, 1H), 7.00 (dd,1H), 6.75 (dd, 1H), 6.40 (d, 1H), 6.38 (s, 1H), 6.23 (d, 1H), 4.35-2.80(series of br m, total 22 H), 3.80 (s, 3H), 1.96 (m, 2H).

EXAMPLE 694-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-morpholin-4-ylphenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 32B for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.63 (s, 1H), 9.86 (s, 1H), 8.71 (t, 1H), 8.50(d, 1H), 7.83 (dd, 1H), 7.70 (s, 1H), 7.50 (m, 5H), 7.39 (d, 2H), 7.32(m, 1H), 7.16 (d, 1H), 7.08 (m, 1H), 6.74 (dd, 1H), 6.59 (dd, 1H), 6.40(m, 2H), 6.23 (dd, 1H), 4.24 (m, 2H), 3.97 (m, 2H), 3.70 (m, 4H), 3.63(m, 4H), 3.54 (m, 4H), 3.18 (m, 4H), 3.07 (m, 4H), 3.00 (m, 4H), 2.83(m, 2H), 1.98 (m, 2H).

EXAMPLE 704-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((3-(3-morpholin-4-yl-3-oxopropyl)-1H-indol-5-yl)oxy)benzamideEXAMPLE 70A (Z)-tert-butyl5-(benzyloxy)-3-(3-morpholino-3-oxoprop-1-enyl)-1H-indole-1-carboxylate

A mixture of tert-butyl 5-(benzyloxy)-3-bromo-1H-indole-1-carboxylate(2.011 g), 1-morpholinoprop-2-in-1-one (0.776 g), palladium acetate (31mg), tri-o-tolylphosphine (187 mg) and triethylamine (1.14 mL) inN,N-dimethylformamide (14 mL) under nitrogen atmosphere was stirred at100° C. overnight. The mixture was diluted with ethyl acetaate andsaturated ammonium chloride. The aqueous layer was extracted with ethylacetate and the combined organic layers were dried over MgSO₄, filteredand concentrated. The residue was purified by flash chromatography (80%ethyl acetate-hexane) to give the desired product.

EXAMPLE 70B tert-butyl5-(benzyloxy)-3-(3-morpholino-3-oxopropyl)-1H-indole-1-carboxylate

The title compound was prepared by substituting EXAMPLE 70A for EXAMPLE39A in EXAMPLE 39B.

EXAMPLE 70C tert-butyl5-(5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(methoxycarbonyl)phenoxy)-3-(3-morpholino-3-oxopropyl)-1H-indole-1-carboxylate

The title compound was prepared by substituting EXAMPLE 70B for EXAMPLE1D in EXAMPLE 1E .

EXAMPLE 70D methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(3-morpholino-3-oxopropyl)-1H-indol-5-yloxy)benzoate

A solution of EXAMPLE 70C (300 mg) in dioxane (2 mL) was treated withconcentrated aqueous hydrogen chloride (0.378 mL) and stirred at roomtemperature overnight. The solution was concentrated and the residue wasused for the next step without further purification.

EXAMPLE 70E4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(3-morpholino-3-oxopropyl)-1H-indol-5-yloxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 70D for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 70F4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((3-(3-morpholin-4-yl-3-oxopropyl)-1H-indol-5-yl)oxy)benzamide

The title compound was prepared by substituting EXAMPLE 70E for EXAMPLE1F and EXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.37 (s, 1H), 10.88 (s, 1H), 9.33 (s, 1H), 8.64(m, 2H), 7.88 (d, 1H), 7.66 (s, 1H), 7.51 (dd, 5H), 7.35 (dd, 3H), 7.29(s, 1H), 7.21 (s, 1H), 7.13 (d, 2H), 6.82 (dd, 1H), 6.67 (d, 1H), 6.21(s, 1H), 3.42 (s, 20H), 3.12 (s, 2H), 2.85 (m, 2H), 2.78 (d, 6H), 2.61(m, 2H), 1.95 (m, 2H).

EXAMPLE 712-(3-benzylxoy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pryan-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 71A2-(3-benzyloxy)phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 33A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 71B2-(3-benzylxoy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pryan-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 71A for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.69 (m,1H), 8.62 (m, 1H), 8.48 (d, 1H), 7.76 (dd, 1H), 7.65 (m, 1H), 7.50 (m,5H), 7.38 (m, 6H), 7.32 (m, 2H), 7.11 (m, 2H), 6.77 (dd, 1H), 6.62 (dd,1H), 6.41 (m, 2H), 6.35 (m, 1H), 4.98 (s, 2H), 3.83 (m, 2H), 3.28 (m,12H), 3.17 (m, 2H), 1.89 (m, 1H), 1.59 (m, 2H), 1.26 (m, 2H).

EXAMPLE 724-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-cyanophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 72A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-cyanophenoxy)benzoate

The title compound was prepared by substituting 4-cyanophenol forEXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 72B 4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-cyanophenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 72A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 72C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-cyanophenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 72B for EXAMPLE1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.97 (s,1H), 9.54 (s, 1H), 8.62 (t, 1H), 8.44 (d, 1H), 7.66 (m, 4H), 7.53 (m,5H), 7.37 (m, 3H), 7.12 (d, 1H), 6.82 (m, 3H), 6.64 (d, 1H), 4.37 (m,1H), 3.86 (dd, 2H), 3.49 (m, 2H), 3.26 (m, 8H), 3.10 (m, 2H), 2.84 (s,1H), 1.92 (m, 1H), 1.64 (dd, 2H), 1.28 (m, 2H).

EXAMPLE 734-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpholin-4-yl-3-oxopropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 70E for EXAMPLE1F in EXAMPLE 1H, ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.38 (s,1H), 10.87 (s, 1H), 8.59 (m, 2H), 7.79 (dd, 1H), 7.68 (s, 1H), 7.51 (dd,5H), 7.34 (dd, 4H), 7.20 (s, 1H), 7.10 (d, 2H), 6.81 (dd, 1H), 6.68 (d,1H), 6.23 (s, 1H), 3.85 (d, 2H), 3.44 (s, 18H), 3.28 (m, 4H), 2.84 (m,2H), 2.60 (t, 2H), 1.89 (s, 1H), 1.63 (m, 2H), L 27 (m, 2H).

EXAMPLE 744-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpholin-4-ylpropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 74A4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpholinopropyl)-1H-indol-5-yl)oxy)benzoate

EXAMPLE 70C (107 mg) was dissolved in anhydrous tetrahydrofuran (0.7mL), followed by the addition of 1M borane in tetrafuran solution (0.57mL). The reaction mixture was stirred at room temperature overnight. Thereaction was quenched with 1N HCl was removed under vacuum. The residuewas purified by flash column chromatography on silica gel using 10-50%ethyl acetate in hexanes to afford the product.

EXAMPLE 74B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpholinopropyl)-1H-indol-5-yl)oxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 74A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 74C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpholin-4-ylpropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 74B for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.35 (m,1H), 10.95 (s, 1H), 9.58 (m, 1H), 8.60 (m, 2H), 7.86 (dd, 1H), 7.63 (m,1H), 7.50 (dd, 5H), 7.35 (t, 3H), 7.28 (s, 1H), 7.22 (dd, 2H), 7.17 (d,1H), 6.84 (d, 1H), 6.65 (d, 1H), 6.16 (s, 1H), 3.93 (s, 1H), 3.84 (d,2H), 3.50 (m, 15H), 3.32 (m, 2H), 3.26 (m, 2H), 3.13 (m, 2H), 3.03 (s,2H), 2.68 (t, 2H), 1.97 (d, 2H), 1.89 (s, 1H), 1.61 (d, 2H), 1.27 (m,2H).

EXAMPLE 754-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 75A 4-((dimethylamino)methyl)phenol

The title compound was prepared by substituting 4-hydroxybenzaldehydefor 4′-chlorobiphenyl-2-carboxaldehyde and dimethylamine fortert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 75B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-((dimethylamino)methyl)phenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 75A for EXAMPLE1D in EXAMPLE 1E.

EXAMPLE 75C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-dimethylamino)methyl)phenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 75B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 75D4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4((dimethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 75C for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.80 (br s,1H), 9.60 (br s, 1H), 8.59 (m, 1H), 8.48 (m, 1H), 7.80 (d, 1H), 7.50 (d,2H), 7.46 (m, 2H), 7.36 (m, 4H), 7.24 (m, 2H), 6.90 (d, 2H), 6.77 (d,1H), 6.44 (d, 1H), 4.16 (m, 2H), 3.84 (dd, 2H), 3.30 (m, 8H), 3.15 (m,4H), 2.68 (m, 4H), 2.35 (m, 4H), 1.88 (m, 1H), 1.61 (dd, 2H), 1.23 (m,2H).

EXAMPLE 764-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-(1H-imidazol-1-yl)-phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 76A methyl2-((4-(1H-imidazol-1-yl)-phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting4-(1H-imidazol-1-yl)phenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 76B2-((4-(1H-imidazol-1-yl)-phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 76A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 76C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-(1H-imidazol-1-yl)-phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 76B for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.50 (s, 1H),8.17 (d, 1H), 7.78 (m, 1H), 7.66 (m, 1H), 7.40-7.58 (m, 8H), 7.37 (d,2H), 7.25 (m, 1H), 7.10 (d, 2H), 6.94 (d, 1H), 6.75 (d, 1H), 6.63 (d,1H), 6.43 (d, 1H), 3.82 (m, 2H), 3.37 (m, 4H), 3.08-3.21 (m, 6H), 2.35(m, 4H), 1.82 (m, 1H), 1.58 (m, 2H), 1.40 (m, 2H).

EXAMPLE 774-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophenoxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 77A4-((tetrahydro-2H-pyran-4-yl)methylamino)phenyl)benzenesulfonamide

4-Aminobenzenesulfonamide (6.80 g), tetrahoydropyran-4-carboxaldehyde(4.96 g), and sodium triacetoxyborohydride (16.74 g) in tetrahydrofuran(300 mL) and acetic acid (15 mL) were stirred at room temperature for 24hours. The reaction was concentrated and taken up in ethyl acetate. Theresulting solution was washed with water and brine, concentrated, andchromatographed on silica gel with 50% ethyl acetate/hexanes.

EXAMPLE 77B4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophenoxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide2,2,2-trifluoroacetate

The title compound was prepared by substituting EXAMPLE 8B for EXAMPLE50F and EXAMPLE 77A for EXAMPLE 3I in EXAMPLE 50G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.58 (br s, 1H), 9.58 (br s, 1H), 7.86 (m, 1H),7.71 (br s, 1H), 7.52 (m, 7H), 7.40 (m, 5H), 7.30 (m, 1H), 6.82 (dd,1H), 6.71 (br s, 1H), 6.60 (d, 1H), 6.47 (d, 2H), 4.37 (v br s, 1H),3.83 (dd, 2H), 3.70 (v br s, 1H), 3.50-3-40 (envelope, 6H), 3.26, (m,2H), 3.05, 2.96, 2.94, 2.85 (all br s, total 4H), 1.79 (m, 1H), 1.65 (m,2H), 1.22 (m, 2H).

EXAMPLE 78 tert-butyl4-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)benzyl(ethyl)carbamateEXAMPLE 78A tert-butyl ethyl(4-hydroxybenzyl)carbamate

Diethylamine gas was bubbled into a solution of 4-hydroxybenzaldehyde(2.0 g) and sodium triacetoxyborohydride (5.2 g) in dichloromethane (60mL) until saturated. The reaction flask was stoppered and the reactionstirred for 24 hours. 1 M NaOH (10 mL) was then added, followed bydi-tert-butyl deicarbonate (3.57 g) and triethylamine (2.28 mL), and thereaction was stirred for 24 hours. The reaction was acidified withsaturated NaH₂PO₄ solution, extracted twice with ethyl acetate, and thecombined extracts were washed with brine and concentrated. The crudeproduct was chromatographed on silica gel using 20% ethylacetate/hexanes as the eluent to give the product.

EXAMPLE 78B methyl2-(4-((tert-butoxycarbonyl(ethyl)amino)methyl)phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 78A for EXAMPLE1D in EXAMPLE 1E .

EXAMPLE 78C2-(4-((tert-butoxycarbonyl(ethyl)amino)methyl)phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoic acid

The title compound was prepared by substituting EXAMPLE 78B for EXAMPLE1E in EXAMPLE 1E.

EXAMPLE 78D tert-butyl4-(5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)benzyl(ethyl)carbamate

The title compound was prepared by substituting EXAMPLE 78C for EXAMPLE1F in EXAMPLE 1H.

EXAMPLE 79 tert-butyl3-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)benzyl(ethyl)carbamateEXAMPLE 79A tert-butyl ethyl(4-hydroxybenzyl)carbamate

The title compound was prepared by substituting 3-hydroxybenzaldehydefor 4-hydroxybenzaldehyde in EXAMPLE 78A.

EXAMPLE 79B methyl2-(3-((tert-butyxoycarbonyl(ethyl)amino)methyl)phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 79A for EXAMPLE1D in EXAMPLE 1E .

EXAMPLE 79C2-(3-((tert-butyxoycarbonyl(ethyl)amino)methyl)phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 79B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 79D tert-butyl3-(5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)benzyl(ethyl)carbamate

The title compound was prepared by substituting EXAMPLE 79C for EXAMPLE1F in EXAMPLE 1H.

EXAMPLE 804-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-((ethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 78D for EXAMPLE1A in EXAMPLE 1B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.63 (br s,1H), 8.52 (br s, 1H), 8.43 (s, 1H), 7.78 (dd, 1H), 7.60 (d, 1H), 7.46(s, 4H), 7.35 (d, 2H), 7.31 (m, 1H), 7.24 (d, 1H), 7.13 (d, 1H), 6.84(d, 2H), 6.72 (d, 1H), 6.36 (s, 1H), 4.04 (s, 2H), 3.84 (dd, 2H), 3.27(m, 6H), 3.11 (m, 4H), 2.94 (m, 2H), 2.36 (m, 4H), 1.91 (m, 1H), 1.62(dd, 2H), 1.23 (m, 2H), 1.17 (t, 3H).

EXAMPLE 814-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((ethylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 79D for EXAMPLE1A in EXAMPLE 1B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.60 (br s,1H), 8.80 (br s, 1H), 8.62 (br s, 1H), 8.51 (s, 1H), 7.82 (dd, 1H),7.30-7.55 (m, 7H), 7.24 (m, 2H), 7.19 (d, 1H), 7.04 (d, 1H), 6.89 (d,1H), 6.77 (d, 1H), 6.36 (s, 1H), 4.06 (s, 2H), 3.86 (dd, 2H), 3.27 (m,6H), 3.11 (m, 4H), 2.96 (m, 2H), 2.34 (m, 4H), 1.90 (m, 1H), 1.61 (dd,2H), 1.24 (m, 2H), 1.19 (t, 3H).

EXAMPLE 822-(4-(acetylamino)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 82A methyl2-(4-acetamidophenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting 4-acetamidophenol forEXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 82B2-(4-acetamidophenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 82A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 82C2-(4-(acetylamino)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 82B for EXAMPLE1G in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.58 (s,1H), 9.91 (s, 1H), 8.62 (t, 1H), 8.54 (d, 1H), 7.76 (dd, 1H), 7.68 (m,1H), 7.51 (m, 7H), 7.34 (m, 3H), 7.16 (d, 1H), 6.85 (d, 2H), 6.72 (dd,1H), 6.30 (m, 1H), 4.35 (s, 1H), 3.85 (dd, 2H), 3.68 (m, 1H), 3.27 (m, 9H), 3.02 (m, 2H), 2.83 (m, 1H), 2.04 (s, 3H), 1.89 (m, 1H), 1.62 (dd,2H), 1.24 (m, 2H).

EXAMPLE 83 tert-butyl4-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenylcarbamate

This EXAMPLE was prepared by substituting EXAMPLE 18B for EXAMPLE 1F inEXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.37 (s, 1H), 9.32(s, 1H), 8.61 (t, 1H), 8.57 (d, 1H), 7.81 (dd, 1H), 7.44 (m, 8H), 7.34(m, 2H), 7.22 (m, 2H), 6.88 (d, 2H), 6.69 (dd, 1H), 6.20 (d, 1H), 3.85(m, 2H), 3.28 (m, 6H), 3.09 (m, 4H), 2.33 (m, 4H), 1.90 (m, 1H), 1.63(m, 2H), 1.47 (m, 9 H), 1.26 (m, 2H).

EXAMPLE 842-(1,1′-biphenyl-2-yloxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 84A methyl2-(biphenyl-2-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting 2-phenylphenol forEXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 84B methyl2-(biphenyl-2-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 84A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 84C2-(1,1′-biphenyl-2-yloxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide2,2,2-trifluoroacetate

The title compound was prepared by substituting EXAMPLE 84B for EXAMPLE50F EXAMPLE 1G for EXAMPLE 3I in EXAMPLE 50G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.56 (v br s, 1H), 9.50 (v br s, 1H), 8.62 (t,1H), 8.45 (d, 1H), 7.76 (dd, 1H) 7.70 (br s, 1H), 7.50 (m, 7H), 7.37 (d,2H), 7.27 (m, 5H), 7.12 (m, 2H), 7.04 (m, 1H), 6.70 (dd, 1H), 6.64 (d,1H), 6.27 (s, 1H), 4.35 (v br s, 1H), 3.83 (dd, 2H), 3.70 (v br s, 1H),3.40 (m, 4H), 3.25, 3.20 (both m, total 4H), 3.00, 2.80 (both br s,total 4H), 1.83 (m, 1H), 1.59 (m, 2H), 1.24 (m, 2H).

EXAMPLE 85 tert-butyl3-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenylcarbamate

The title compound was prepared as described in EXAMPLE 19C. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.45 (s, 1H), 9.34 (s, 1H), 8.62 (t, 1H),8.52 (d, 1H), 7.75 (dd, 1H), 7.46 (m, 6H), 7.36 (m, 2H), 7.23 (m, 1H),7.11 (m, 4H), 6.74 (dd, 1H), 6.42 (m, 1H), 6.36 (d, 1H), 3.86 (dd, 2H),3.30 (m, 6H), 3.15 (m, 4H), 2.35 (m, 4H), 1.90 (qd, 1H), 1.63 (dd, 2H),1.45 (s, 9 H), 1.27 (m, 2H).

EXAMPLE 862-(1,1′-biphenyl-3-yloxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 86A methyl2-(biphenyl-3-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting 3-phenylphenol forEXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 86B2-(biphenyl-3-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 86A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 86C2-(1,1′-biphenyl-3-yloxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide2,2,2-trifluoroacetic

The title compound was prepared by substituting EXAMPLE 86B for EXAMPLE50F and EXAMPLE 1G for EXAMPLE 3I in EXAMPLE 50G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.82 (v br s, 1H), 9.60 (v br s, 1H), 8.72 (t,1H), 8.42 (d, 1H), 7.70 (br s, 1H), 7.69 (dd, 1H), 7.55-7.20 (m, 15H),7.00 (d, 1H), 6.96 (s, 1H), 6.80 (m, 2H), 6.53 (d, 1H), 4.35 (v br s,1H), 3.83 (dd, 2H), 3.70 (v br s, 1H), 3.40 (m, 4H), 3.25, 3.20 (both m,total 4H), 3.00, 2.80 (both br s, total 4H), 1.81 (m, 1H), 1.58 (m, 2H),1.22 (m, 2H).

EXAMPLE 874-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 87A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)ethyl)phenoxy)benzoate

The title compound was prepared by substituting4-(2-(dimethylamlno)ethyl)phenol for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 87B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)ethyl)phenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 87A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 87C4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 87B for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.67 (s,1H), 9.51 (s, 1H), 8.66 (t, 1H), 8.52 (d, 1H), 7.84 (dd, 1H), 7.70 (s,1H), 7.51 (dd, 5H), 7.36 (m, 3H), 7.22 (m, 3H), 6.84 (d, 2H), 6.76 (m,1H), 6.42 (s, 1H), 3.85 (m, 2H), 3.52 (s, 10H), 3.35 (m, 2H), 3.26 (dd,4H), 2.90 (m, 2H), 2.83 (d, 6H), 1.91 (s, 1H), 1.61 (d, 2H), 1.27 (dt,2H).

EXAMPLE 882-(4-(benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 88A Methyl2-(4-(benzyloxy)phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting 4-(benzyloxy)phenol forEXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 88B2-(4-(benzyloxy)phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 88A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 88C2-(4-(benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 88B for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.50 (m,1H), 8.63 (t, 1H), 8.55 (d, 1H), 7.82 (dd, 1H), 7.66 (m, 1H), 7.41 (m,13H), 7.20 (m, 1H), 6.96 (d, 2H), 6.88 (d, 2H), 6.70 (dd, 1H), 6.25 (m,1H), 5.04 (m, 2H), 3.27 (m, 10 H), 2.90 (m, 6H), 1.88 (m, 1H), 1.57 (m,2H), 1.23 (m, 2H).

EXAMPLE 894-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-morpholin-4-ylphenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 32B for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.58 (s,1H), 8.63 (t, 1H), 8.49 (d, 1H), 7.78 (dd, 1H), 7.69 (m, 1H), 7.52 (m,5H), 7.38 (d, 2H), 7.33 (m, 1H), 7.15 (d, 1H), 7.07 (m, 1H), 6.74 (dd,1H), 6.58 (dd, 1H), 6.40 (m, 2H), 6.22 (dd, 1H), 4.29 (m, 2H), 3.86 (m,2H), 3.70 (m, 6H), 3.30 (m, 6H), 3.00 (m, 6H), 2.83 (m, 2H), 1.91 (m,1H), 1.63 (d, 2H), 1.28 (m, 2H).

EXAMPLE 904-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-1,3-benzothiazol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 24B for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.83 (s,1H), 9.48 (br s, 1H), 8.64 (t, 1H), 8.45 (d, 1H), 7.88 (d, 1H), 7.76(dd, 1H), 7.50 (m, 5H), 7.37 (m, 2H), 7.30 (m, 1H), 7.18 (m, 1H), 7.04(d, 1H), 6.97 (dd, 1H), 6.78 (dd, 1H), 6.48 (br s, 1H), 3.84 (dd, 2H),3.37 (m, 6H), 3.23 (m, 4H), 2.89 (m, 2H), 2.75 (s, 3H), 2.36 (m, 3H),1.62 (d, 2H), 1.24 (m, 2H).

EXAMPLE 91 tert-butyl4-(3-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenyl)piperazine-1-carboxylateEXAMPLE 91A tert-butyl4-(3-(5-(4-((4-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(methoxycarbonyl)phenoxy)phenyl)piperazine-1-carboxylate

The title compound was prepared by substituting1-(3-hydroxy-phenyl)-piperazine-4carboxylic acid tert-butyl ester forEXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 91B2-(3-(4-(tert-butyxoycarbonyl)piperazin-1-yl)phenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 91A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 91C tert-butyl4-(3-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenoxy)phenyl)piperazine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 91B for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.65 (s,1H), 8.65 (t, 1H), 8.47 (d, 1H), 7.76 (dd, 1H), 7.72 (m, 1H), 7.50 (m,5H), 7.37 (d, 2H), 7.33 (m, 1H), 7.15 (d, 1H), 7.05 (m, 1H), 6.75 (dd,1H), 6.57 (dd, 1H), 6.41 (m, 2H), 6.21 (dd, 1H), 4.31 (m, 2H), 3.86 (dd,2H), 3.41 (m, 6H), 3.34 (t, 2H), 3.27 (m, 4H), 3.00 (m, 6H), 2.85 (m,2H), 1.91 (m, 1H), 1.63 (d, 2H), 1.40 (m, 9 H), 1.28 (m, 2H).

EXAMPLE 922-(3-(benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 71A for EXAMPLE1F and EXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.72 (s, 1H), 9.52 (s, 1H), 8.69 (t, 1H), 8.50(d, 1H), 7.81 (dd, 1H), 7.65 (s, 1H), 7.50 (m, 5H), 7.39 (m, 6H), 7.32(m, 2H), 7.13 (m, 2H), 6.77 (dd, 1H), 6.64 (dd, 1H), 6.42 (s, 2H), 6.38(m, 1H), 4.99 (s, 2H), 3.50 (m, 10H), 3.11 (m, 4H), 2.77 (s, 6H), 1.95(m, 2H).

EXAMPLE 932-(3-(benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 71A for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G is EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.74 (m, 1H), 9.78 (s, 1H), 8.71 (m, 1H), 8.50(d, 1H), 7.82 (dd, 1H), 7.67 (s, 1H), 7.50 (m, 5H), 7.39 (m, 6H), 7.32(m, 2H), 7.13 (m, 1H), 6.77 (dd, 1H), 6.64 (dd, 1H), 6.39 (m, 3H), 4.99(s, 2H), 3.96 (m, 2H), 3.60 (s, 2H), 3.51 (m, 6H), 3.17 (m, 10H), 2.67(m, 2H), 1.94 (m, 2H).

EXAMPLE 944-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morpholin-4-ylethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 94A 4-(2-(4-(benzyloxy)phenoxy)ethyl)morpholine

The title compound was prepared by substituting4-(2-chloroethyl)morpholine for 2-chloro-N,N-dimethylethanamine and4-(benzyloxy)phenol for 3-(benzyloxy)phenol in EXAMPLE 39A.

EXAMPLE 94B 4-(2-morpholinoethoxy)phenol

The title compound was prepared by substituting EXAMPLE 94A for EXAMPLE39A in EXAMPLE 39B.

EXAMPLE 94C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morpholinoethoxy)phenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 94B for EXAMPLE1D in EXAMPLE 1E.

EXAMPLE 94D4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morpholinoethoxy)phenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 94C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 94E4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morpholin-4-ylethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 94D for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.46 (m,1H), 9.98 (m, 1H), 8.64 (d, 1H), 8.55 (d, 1H), 7.87 (d, 1H), 7.49 (m,5H), 7.39 (d, 2H), 7.31 (s, 1H), 7.25 (d, 1H), 6.96 (m, 5H), 6.71 (d,1H), 6.29 (s, 1H), 4.30 (s, 2H), 3.98 (s, 2H), 3.85 (d, 2H), 3.72 (s,2H), 3.42 (s, 16H), 3.27 (m, 2H), 1.91 (s, 1H), 1.62 (d, 2H), 1.28 (m,2H).

EXAMPLE 954-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)benzamide

The title compound was prepared by substituting EXAMPLE 58B for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.50 (s,1H), 10.07 (s, 1H), 8.60 (t, 1H), 8.47 (d, 1H), 7.74 (dd, 1H), 7.46 (m,6H), 7.36 (m, 2H), 7.24 (m, 1H), 7.14 (d, 1H), 6.92 (t, 1H), 6.74 (dd,1H), 6.51 (d, 1H), 6.35 (d, 1H), 6.13 (d, 1H), 3.86 (dd, 2H), 3.36 (m,4H), 3.25 (m, 2H), 3.16 (m, 4H), 2.83 (t, 2H), 2.41 (dd, 2H), 2.35 (m,4H), 1.90 (m, 1H), 1.64 (dd, 2H), 1.28 (m, 2H).

EXAMPLE 962-(4-benzyloxy)phenoxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared bys substituting EXAMPLE 88B for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.53 (s, 1H), 9.74 (s, 1H), 8.69 (m, 1H), 8.59(d, 1H), 7.90 (dd, 1H), 7.67 (m,1H), 7.41 (m, 13H), 7.21 (d, 1H), 6.99(m, 2H), 6.91 (m, 2H), 6.70 (dd, 1H), 6.23 (s, 1H), 5.07 (s, 2H), 4.28(m, 2H), 3.95 (s, 2H), 3.51 (m, 6H), 3.16 (m, 10H), 2.73 (d, 2H), 1.98(m, 2H).

EXAMPLE 97 tert-butyl4-(4-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)amino)carbonyl)phenoxy)phenyl)piperazine-1-caraboxylateEXAMPLE 97A tert-butyl4-(4-(5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(methoxycarbonyl)phenoxy)phenyl)piperazine-1-caraboxylate

The title compound was prepared by substituting1-(4-hydroxy-phenol)-piperazine-4-carboxylic acid tert-butyl ester forEXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 97B2-(4-(4-tert-butoxycarbonyl)piperazin-1-yl)phenoxy)-4-(4-(4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 97A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 97C tert-butyl4-(4-(5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)amino)carbonyl)phenoxy)phenyl)piperazine-1-caraboxylate

The title compound was prepared by substituting EXAMPLE 97B for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.44 (m, 1H), 9.67 (s, 1H), 8.70 (t, 1H), 8.59(d, 1H), 7.91 (dd, 1H), 7.69(s, 1H), 7.49 (m, 7H), 7.30 (m, 1H), 7.21(d, 1H), 6.91 (m, 4H), 6.69 (dd, 1H), 6.24 (s, 1H), 3.95 (m, 2H), 3.67(m, 4H), 3.52 (m, 10H), 3.17 (s, 4H), 3.04 (m, 10H), 1.97 (d, 2H), 1.43(s, 9 H).

EXAMPLE 984-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-pyridin-4-ylphenoxy)benzamideEXAMPLE 98A 4-(3-(benzyloxy)phenyl)pyridine

The title compound was prepared by substituting1-(benzyloxy)-3-bromobenzene for EXAMPLE 33C and pyridin-4-ylboronicacid for2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole inEXAMPLE 33D.

EXAMPLE 98B 3-(pyridin-4-yl)phenol

The title compound was prepared by substituting EXAMPLE 98A for EXAMPLE33A in EXAMPLE 33B.

EXAMPLE 98C methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-pyridin-4-ylphenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 98B for EXAMPLE1D in EXAMPLE 1E.

EXAMPLE 98D4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-pyridin-4-ylphenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 98C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 98E4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-pyridin-4-ylphenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 98D for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.87 (m, 1H), 8.68 (d, 2H), 8.58 (m, 1H), 8.42(d, 1H), 7.73 (m, 4H), 7.52 (m, 5H), 7.36 (m, 6H), 7.14 (s, 1H), 7.03(d, 1H), 6.91 (m, 1H), 6.80 (dd, 1H), 6.55 (d, 1H), 4.22 (m, 2H), 3.89(m, 7H), 3.41 (m, 4H), 3.15 (m, 4H), 2.91 (m, 4H), 1.94 (m, 2H).

EXAMPLE 994-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-4-ylphenoxy)benzamideEXAMPLE 99A 4-(4-(benzyloxy)phenyl)pyridine

The title compound was prepared by substituting1-(benzyloxy)-4-bromobenzene for EXAMPLE 33C and pyridin-4-ylboronicacidfor2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole inEXAMPLE 33D.

EXAMPLE 99B 4-(pyridin-4-yl)phenol

The title compound was prepared by substituting EXAMPLE 99A for EXAMPLE33A in EXAMPLE 33B.

EXAMPLE 99C methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(pyridin-4-ylphenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 99B for EXAMPLE1D in EXAMPLE 1E.

EXAMPLE 99D4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(pyridin-4-yl)phenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 99C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 99E4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-4-ylphenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 99D for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.80 (d, 2H), 8.55 (m, 1H), 8.49 (d, 1H), 7.93(m, 5H), 7.74 (m, 1H), 7.53 (m, 5H), 7.36 (m, 3H), 7.13 (m, 2H), 6.93(d, 1H), 6.83 (dd, 1H), 6.62 (d, 1H), 4.60 (s, 4H), 4.29 (m, 2H), 3.67(s, 4H), 3.42 (m, 4H), 3.13 (m, 4H), 2.92 (m, 4H), 1.90 (m, 2H).

EXAMPLE 1004-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-3-ylphenoxy)benzamideEXAMPLE 100A 3-(4-(benzyloxy)phenyl)pyridine

The title compound was prepared by substituting1-(benzyloxy)-4-bromobenzene for EXAMPLE 33C and pyridin-3-ylboronicacid for2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole inEXAMPLE 33D.

EXAMPLE 100B 4-(pyridin-4-yl)phenol

The title compound was prepared by substituting EXAMPLE 100A for EXAMPLE33A in EXAMPLE 33B.

EXAMPLE 100C methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(pyridin-4-ylphenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 100B for EXAMPLE1D in EXAMPLE 1E.

EXAMPLE 100D4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(pyridin-4-ylphenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 100C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 100E4-(4-((4′chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-3-ylphenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 100D for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.84 (s, 1H), 8.95 (d, 1H), 8.66 (d, 1H), 8.57(m, 1H), 8.52 (d, 1H), 8.24 (d, 1H), 7.83 (dd, 1H), 7.72 (m, 5H), 7.53(m, 5H), 7.35 (m, 3H), 7.11 (m, 1H), 6.93 (d, 2H), 6.81 (dd, 1H), 6.57(d, 1H), 4.31 (s, 2H), 3.80 (m, 8H), 3.42 (m, 4H), 3.14 (m, 8H), 1.94(m, 2H).

EXAMPLE 1014-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 101A 2-(4-(benzyloxy)phenoxy)-N,N-dimethylacetamide

The title compound was prepared by substituting2-chloro-N,N-dimethylacetamide for 2-chloro-N,N-dimethylethanamine and4-(benzyloxy)phenol for 3-(benzyloxy)phenol in EXAMPLE 39A.

EXAMPLE 101B 2-(4-hydroxyphenoxy)-N,N-dimethylacetamide

The title compound was prepared by substituting EXAMPLE 101A for EXAMPLE39A in EXAMPLE 39B.

EXAMPLE 101C methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)-2-oxoethoxy)phenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 101B for EXAMPLE1D in EXAMPLE 1E.

EXAMPLE 101D4-(4-((4′chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)-2-oxoethoxy)phenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 101C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 101E4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 101D for EXAMPLE1F to EXAMPLE 1H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 8.68 (t, 1H),8.57 (d, 1H), 7.87 (dd, 1H), 7.72 (s, 1H), 7.53 (dd, 4H), 7.34 (m, 4H),7.16 (d, 1H), 6.84 (m, 4H), 6.71 (dd, 1H), 6.34 (d, 1H), 4.60 (s, 2H),3.84 (d, 2H), 3.51 (s, 10H), 3.36 (m, 2H), 3.26 (m, 2H), 2.81 (d, 6H),1.91 (s, 1H), 1.62 (d, 2H), 1.28 (m, 2H).

EXAMPLE 1024-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1H-benzimidazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-benzamideEXAMPLE 102A methyl4-bromo-2-(1-methyl-1H-benzo[d]imidazol-5-yloxy)benzoate

1-methyl-1H-benzo[d]imidazol-5-ol (296 mg), methyl4-bromo-2-fluorobenzoate (311 mg) and potassium carbonate (553 mg) werecombined in dimethylsulfoxide and ehated to 90° C. overnight. Thereaction mixture was diluted with ethyl acetate and washed thoroughlywith water and with brine, dried voer MgSO₄, filtered and concentrated.

EXAMPLE 102B methyl4-(4-((2-(4-chlorobiphenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(1-methyl-1H-benzo[d]imidazol-5-yloxy)benzoate

EXAMPLE 102A (480 mg) and EXAMPLE 1B (457 mg) were taken up indimethoxyethane (7.5 mL) in a microwave vial.Tris(dibenzylideneacetone)dipalladium(0) (37 mg),2-(di-tert-butylphosphino)biphenyl (48 mg) and potassium phosphatetribasic (423 mg) were added. The vial was capped and heated in a CEMDiscover microwave reactor for 30 minutes at 150° C. The crude reactionmixture was filtered through celite and concentrated. The material wasdissovled in 1:1 dimethylsulfoxide:methanol and purified by HPLC.

EXAMPLE 102C4-(4-((2-(4-chlorobiphenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(1-methyl-1H-benzo[d]imidazol-5-yloxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 102B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 102D4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1H-benzimidazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-benzamide

The title compound was prepared by substituting EXAMPLE 102C for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₆) δ 9.34 (d, 1H), 8.99 (t, 1H), 8.91 (s, 1H), 8.55 (s, 1H),8.48 (dd, 1H), 7.94 (t, 1H), 7.50 (m, 4H), 7.42 (m, 3H), 7.35 (m, 3H),7.05 (s, 1H), 7.02 (d, 1H), 6.70 (m, 2H), 3.79 (t, 4H), 3.39 (s, 3H),3.35 (m, 2H), 3.15 (m, 4H), 2.36 (m, 12H), 1.74 (m, 2H).

EXAMPLE 1034-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylcarbamoyl)phenoxy)-N-(4-(3-morpholinopropylamino-3-nitrophenylsulfonyl)benzamideEXAMPLE 103A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylcarbamoyl)phenoxy)benzoate

The title compound was prepared by substituting3-hydroxy-N-methylbenzamide for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 103B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylcarbamoyl)phenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 103A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 103C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylcarbamoyl)phenoxy)-N-(4-(3-morpholinopropylamino-3-nitrophenylsulfonyl)benzamidebis(2,2,2-trifluoroacetate)

The title compound was prepared by substituting EXAMPLE 103B for EXAMPLE50F and EXAMPLE 4A for EXAMPLE 3I in EXAMPLE 50G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.79 (v br s, 1H), 9.38 (v br s, 1H), 8.65 (t,1H), 8.48 (d, 1H), 8.37 (q, 1H), 7.78 (dd, 1H), 7.70 (br s, 1H), 7.50(m, 6H), 7.35 (m, 4H), 7.26 (s, 1H), 7.11 (d, 1H), 6.98 (dd, 1H), 6.79(dd, 1H), 6.43 (s, 1H), 4.35 (v br s, 1H), 3.99 (br m, 2H), 3.70 (v brs, 1H), 3.60, 3.50, 3.40 (all br m, total 10H), 3.20, 310, 2.80 (all brs, total 8M), 2.79, 2.77 (both s, total 3H), 1.99 (m, 2H).

EXAMPLE 1044-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propylamino)-3-nitrophenylsulfonyl)-2-(3-(methylcarbamoyl)phenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 103B for EXAMPLE50F and EXAMPLE 11A for EXAMPLE 3I in EXAMPLE 50G. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.79 (v br s, 1H), 9.38 (v br s, 1H), 8.65 (t,1H), 8.48 (d, 1H), 8.37 (q, 1H), 7.78 (dd, 1H), 7.70 (br s, 1H), 7.50(m, 6H), 7.39 (m, 2H), 7.31 (m, 2H), 7.26 (s, 1H), 7.11 (d, 1H), 6.98(dd, 1H), 6.79 (dd, 1H), 6.43 (s, 1H), 4.35 (v br s, 1H), 3.80 (v br s,1H), 3.50, (br m, 8H), 3.10, 3.05 (m, br s, 4H), 2.81, 2.80 (both s,6H), 2.78, 2.77 (both s, 3H), 1.96 (m, 2H).

EXAMPLE 1054-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 105A 2-(3-(benzyloxy)phenoxy)-N,N-dimethylacetamide

The title compound was prepared by substituting2-chloro-N,N-dimethylacetamide for 2-chloro-N,N-dimethylethanamine inEXAMPLE 39A.

EXAMPLE 105B 2-(3-hydroxyphenoxy)-N,N-dimethylacetamide

The title compound was prepared by substituting EXAMPLE 105A for EXAMPLE39A in EXAMPLE 39B.

EXAMPLE 105C

methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)-2-oxoethoxy)phenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 105B for EXAMPLE1D in EXAMPLE 1E.

EXAMPLE 105D4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)-2-oxoethoxy)phenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 105C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 105E4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 105D for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 8.66 (d, 1H),8.54 (d, 1H), 7.84 (dd, 1H), 7.72 (s, 1H), 7.51 (m, 5H), 7.35 (m, 3H),7.28 (t, 1H), 7.16 (dd, 2H), 6.75 (dd, 1H), 6.46 (m, 3H), 4.60 (s, 2H),3.83 (d, 2H), 3.48 (s, 10H), 3.34 (m, 2H), 3.24 (m, 2H), 2.78 (s, 6H),1.89 (s, 1H), 1.60 (d, 2H), 1.26 (m, 2H).

EXAMPLE 1064-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(dimethylamino)propyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 106A (Z)-tert-butyl5-(benzyloxy)-3-(3-(dimethylamino)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate

The title compound was prepared by substituting N,N-dimethylacrylamidefor 1-morpholinoprop-2-en-1-one in EXAMPLE 70A.

EXAMPLE 106B tert-butyl3-(3-(dimethylamino)-3-oxopropyl-5-hydroxy-1H-indole-1-carboxylate

The title compound was prepared by substituting EXAMPLE 106A for EXAMPLE39A in EXAMPLE 39B.

EXAMPLE 106C tert-butyl5-(5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(methoxycarbonyl)phenoxy)-3-(3-(dimethylamino)-3-oxopropyl)-1H-indole-1-carboxylate

The title compound was prepared by substituting EXAMPLE 106B for EXAMPLE1D in EXAMPLE 1E.

EXAMPLE 106D methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(3-(dimethylamino)propyl)-1H-indol-5-yloxy)benzoate

The title compound was prepared by substituting EXAMPLE 106C for EXAMPLE70C in EXAMPLE 74A.

EXAMPLE 106E4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(3-(dimethylamino)propyl)-1H-indol-5-yloxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 106D for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 106F4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(dimethylamino)propyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 106E for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 10.97 (d,1H), 9.34 (s, 1H), 8.61 (m, 2H), 7.86 (dd, 1H), 7.54-7.36 (m, 8H), 7.22(m, 4H), 6.86 (m, 1H), 6.67 (dd, 1H), 6.16 (d, 1H), 3.83 (m, 2H),3.34-3.24 (m, 8H), 3.07 (m, 6H), 2.76 (s, 6H), 2.67 (m, 2H), 1.95 (m,3H), 1.65 (m, 2H), 1.29 (m, 4H), 0.88 (m, 2H).

EXAMPLE 1074-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-(hydroxymethyl)phenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 9A for EXAMPLE50F and EXAMPLE 11A for EXAMPLE 3I in EXAMPLE 50G. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.60 (v br s, 1H), 9.40 (v br s, 1H)s 8.76 (t,1H), 8.51 (d, 1H), 7.80 (dd, 1H), 7.65 (br s, 1H), 7.50 (m, 5H), 7.40(m, 2H), 7.30 (br s, 1H), 7.20 (dd, LH), 7.16 (d, 1H), 6.96 (d, 1H),6.82 (s, 1H), 6.65 (d, 1H), 6.60 (d, 1H), 6.40 (s, 1H), 4.41 (s, 2H),3.55 (m 4H), 3.40, (m, 6H), 3.13 (m, 4H), 2.80, 2.79 (both s, total 6H),1.98 (m, 2H).

EXAMPLE 1084-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-methoxybenzyl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamideEXAMPLE 108A 4-Fluoro-2-(4-methoxy-benzyloxy)-benzoic acid methyl ester

Methyl 4-fluoro-2-hydroxybenzoate (1661 mg) was added toN,N-dimethylformamide (50 mL). Sodium hydride (60%) in mineral oil, 430mg) was added, the solution stirred for 15 minutes at room temperature,and 1-(bromomethyl)-4-methoxybenzene (2061 mg) was added. The solutionwas stirred at room temperature for three days, added to 0.01M aqueousHCl, and extracted with ethyl acetate. The organic phase was washed withwater twice washed with brine, and dried over anhydrous sodium sulfate.After filtration, the solvent was removed under vacuum.

EXAMPLE 108B4-[4-(4′-Chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-2-(4-methoxy-benzyloxy)-benzoicacid methyl ester

The title compound was prepared by substituting EXAMPLE 108A for methyl2-bromo-4-fluorobenzoate in EXAMPLE 1C.

EXAMPLE 108C4-[4-(4′-Chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-2-(4-methoxy-benzyloxy)-benzoicacid

The title compound was prepared by substituting EXAMPLE 108B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 108D4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-methoxybenzyl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 108C for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 10.79 (br s,1H), 8.65 (t, 1H), 8.58 (d, 1H), 7.82 (dd, 1H), 7.53-7.41 (m, 7H), 7.38(m, 2H), 7.27-7.19 (m, 2H), 6.98 (d, 2H), 6.69 (br s, 1H), 6.55 (dd,1H), 5.16 (s, 2H), 3.84 (dd, 2H), 3.78 (s, 3H), 3.40 (s, 2H), 3.37-3.32(m, 8H), 2.38 (m, 4H), 1.90 (m, 1H), 1.62 (dd, 2H), 1.26 (m, 2H).

EXAMPLE 109N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamideEXAMPLE 109A4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide

A mixture of 4-chloro-3-nitrobenzenesulfonamide,4-(aminomethyl)tetrahydro-2H-pyran-4-amine, hydrochloric acid andtriethylamine in dioxane (10 mL) was heated at 110° C. overnight. Aftercooling, the mixture was diluted with water (10 mL), and filtered.

EXAMPLE 109BN-(4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrophenylsulfonyl)-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

This example was prepared by substituting EXAMPLE 6B for EXAMPLE 1F andEXAMPLE 109A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, DMSO-d₆) δ8.41 (s, 1H), 8.35 (d, J=1.83 Hz, 1H), 7.70 (dd, J=9.0, 1.98 Hz, 1H),7.64 (d, j=8.85 Hz, 1H), 7.36 (d, J=8.54 Hz, 2H), 7.11-7.18 (m, 2H),7.07 (d, J=8.24 Hz, 2H), 6.91 (dd, J=7.93, 1.22 Hz, 1H), 6.77 (dd,J=8.85, 2.14 Hz, 1H), 6.65 (dd, J=8.09, 1.98 Hz, 1H), 6.61-6.62 (m, 1H),6.38 (d, J=2.14 Hz, 1H), 3.67-3.71 (m, 6H), 3.11 (m, 3H), 2.77 (s, 2H),2.18-2.24 (m, 6H), 1.97-1.99 (m, 2H), 1.76-1.79 (m, 2H), 1.65-1.67 (m,2H), 1.39-1.42 (m, 2H), 0.94 (s, 6H).

EXAMPLE 1104-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(2-chlorophenoxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 110A 1-(4′-chlorobiphenyl-2-yl)ethanone

A mixture of 1-(2-bromophenyl)ethanone (3.1 g) 4-chlorophenylboronicacid (2.92 g), bis(triphenylphosphine)palladium(II) dichloride (1.202 g)and Na₂CO₃ (3.30 g) in 7:2:3 dimethoxyethane/ethanol/water (50 mL) washeated at 100° C. for 3 hours and concentrated. The concentrate wassuspended in dichloromethane (30 mL) and filtered. The filtrate wasloaded onto a silica gel column and flash chromatographed with 0%-50%dichlommethane/hexane.

EXAMPLE 110B tert-butyl4-(1-(4′-chlorobiphenyl-2-yl)ethyl)piperazine-1-carboxylate

A mixture of EXAMPLE 110A (1.9 g) in dichloromethane (3 mL) was treatedwith 1M titanium(IV) chloride in dichloromethane (9.06 mL), cooled to 0°C., treated with tert-butyl piperazine-1-carboxylate (3.07 g), stirredat ambient temperature for 3 hours, treated with NaCNBH₃ (0.828 g) inmethanol (5 ml), stirred at room temperature overnight, neutralized withaqueous NaOH and concentrated. The concentrate was treated with ethylacetate and filtered. The organic filtrate was washed with water andconcentrated. The concentrate was dissolved in methanol/trifluoroaceticacid/dimethylsulfoxide, loaded onto a reverse phase C18 column andeluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over70 minutes.

EXAMPLE 110C 1-(1-(4′-chlorobiphenyl-2-yl)ethyl)piperazine

To a solution of EXAMPLE 110B (650 mg) in dichloromethane (6 mL) at 0°C. was added trifluoroacetic acid (6 mL). The mixture was stirred at 0°C. for 50 minutes and concentrated. The concentrate was dissolved indichloromethane, washed with aqueous NaHCO₃ and dried over Na₂SO₄,filtered and concentrated.

EXAMPLE 110D ethyl4-(4-(1-(4′-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)-2-(2-chlorophenoxy)benzoate

EXAMPLE 110C (252 mg) and ethyl 2-(2-chlorophenoxy)-4-fluorobenzoate(272 mg) in dimethylsulfoxide (15 mL) was treated with potassiumhydrogenphosphate (219 mg), stirred at 135° C. overnight, cooled,diluted with dichloromethane, washed with water and concentrated. Theconcentrate was dissolved in dichloromethane, loaded onto a silica gelcolumn and eluted with 5% 10M ammonia methanol in dichloromethane.

EXAMPLE 110E4-(4-(1-(4′-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)-2-(2-chlorophenoxy)benzoicacid

A mixture of EXAMPLE 110D (300 mg) in tetrahydrofuran (10 mL) andmethanol (10 mL) at 50° C. was treated with 10% NaOH (2085 μL), stirredovernight, neutralized with HCl and concentrated. The concentrate wastaken up in water and extracted with dichloromethane. The organic layerwas dried over Na₂SO₄, filtered and concentrated.

EXAMPLE 110F4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(2-chlorophenoxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

To a mixture of EXAMPLE 110E (65 mg), Example 1G (74.9 mg) and4-dimethylaminopyridine (58 mg) in dichloromethane (5 mL) was added1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (45.5mg). The mixture was stirred at ambient temperature overnight andconcentrated. The concentrate was purified by RP HPLC (10-70%acetonitrile 0.1% trifluoroacetic acid water/70 min). Fractionscontaining product were conenctrated, and the concentrate was dilutedwith dichloromethane, neutralized with aqueous NaHCO₃, dried overNa₂SO₄, filtered, and concentrated. ¹H NMR (500 MHz, DMSO-d₆) δ 11.58(s, 1H), 8.64 (t, 1H), 8.47 (d, 1H), 7.78 (dd, 1H), 7.56 (d, 1H),7.45-7.52 (m, 3H), 7.38-7.43 (m, 2H), 7.27-7.33 (m, 3H), 7.11-7.19 (m,3H), 6.99 (t, 1H), 6.70-6.77 (m, 2H), 6.28 (d, 1H), 3.86 (dd, 2H),3.33-3.37 (m, 1H), 3.24-3.31 (m, 4H), 3.12 (s, 4H), 2.33-2.47 (m, 2H),2.20-2.31 (m, 2H), 1.85-1.96 (m, 1H), 1.64 (d, 2H), 1.17-1.33 (m, 5H)

EXAMPLE 111N-{[4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]-3-nitrobenzamideEXAMPLE 111A 4-(1-methylpiperidin-4-ylamino)-3-nitrobenzoic acid

To a solution of ethyl 4-fluoro-3-nitrobenzoate (2.13 g) and1-methylpiperidin-4-amine (1.14 g) in tetrahydrofuran (40 mL) was addedN,N-diisopropylethylamine (5 mL). The mixture was then stirred at refluxovernight. The solvent was evaporated and the resiude was dissolved inethyl acetate (300 mL) and washed with aqueous NaHCO₃, water and brine.After evaporation of the solvent, the residue was dissolved intetrahydrofuran (20 mL), methanol (10 mL) and water (10 mL). Then, LiOHH₂O (2 g) was added. The mixture was stirred at room temperatureovernight. The mixture was then concentrated and the resiude wasneutralized with 5% aqueous HCl. The precipitate was filtered, washedwith brine, and dried under vacuum to give the product.

EXAMPLE 111B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-fluorobenzenesulfonamide

To a solution of 2.4-difluorobenzenesulfonamide (1.56 g) and1-((4′-chlorobiphenyl-2-yl)methyl)piperazine (2.32 g) indimethylsulfoxide (20 mL) was added N,N-diisopropylethylamine (5 mL).The mixture was stirred at 120° C. overnight. The mixture was dilutedwith ethyl acetate (300 mL) and washed with water (3×) brine and driedover Na₂SO₄. After filtration and evaporation of the solvent, theresidue was loaded on a column and eluted with 40% ethyl acetate inhexane to give the title compound.

EXAMPLE 111C

4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-fluorobenzenesulfonyl)-4-(1-methylpiperidin-4-ylamino)-3-nitrobenzamide

The title compound was prepared as described in EXAMPLE 1G by replacingEXAMPLE 1E and EXAMPLE 1F with EXAMPLE 111A and EXAMPLE 111B,respectively.

EXAMPLE 111DN-{[4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]-3-nitrobenzamide

To a solution of 3,5-dichlorophenol (81 mg) and EXAMPLE 111C (72 mg) indiglyme (3 mL) was added K₂HPO₄ (53 mg). The mixture was stirred at 200°C. in a CEM Discover microwave reactor for 2 hours. The mixture wasfiltered and purified by RP HPLC (10-70% acetonitrile in 0.1%trifluoroacetic acid water/70 min). Fractions containing product wasconcentrated, and the concentrate was diluted with dichloromethane,neutralized with aqueous NaHCO₃, dried over Na₂SO₄, filtered, andconcentrated. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.56 (d, 1H),8.12 (d, 1H), 7.94 (m, 1H), 7.84 (m, 2H), 7.51 (m, 514), 7.36 (m, 4H),7.17 (d, 1H), 7.05 (m, 1H), 6.94 (m, 1H), 6.71 (m, 1H), 4.36 (m, 1H),3.92 (m, 2H), 3.15 (m, 4H), 2.79 (m, 6H), 2.22 (m, 8H), 1.29 (m, 2H).

EXAMPLE 1124-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 112A ethyl 4-fluoro-2-(3-fluorophenoxy)benzoate

The title compound was prepared by substituting 3-fluorophenol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 112B ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-fluorophenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 112A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 112C 4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-fluorophenoxy)benzoic acid

The title compound was prepared by substituting EXAMPLE 112B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 112D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.34 (d, 1H), 8.08 (d, 1H), 7.69 (dd, 1H), 7.60(d, 1H), 7.36 (d, 2H), 7.14 (m, 1H), 7.06 (d, 2H), 7.03 (d, 1H), 6.72(dd, 1H), 6.65 (m, 1H), 6.49 (dd, 1H), 6.41 (m, 2H), 3.81 (m, 1H), 3.22(m, 2H), 3.11 (m, 4H), 2.88 (m, 2H), 2.77 (m, 2H), 2.64 (s, 3H), 2.22(m, 6H), 2.10 (m, 2H), 1.98 (m, 2H), 1.79 (m, 2H), 1.40 (m, 2H), 0.94(s, 6H).

EXAMPLE 1134-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.34 (d, 1H), 8.10 (d, 1H), 7.67 (dd, 1H), 7.60(d, 1H), 7.36 (d, 2H), 7.14 (m, 1H), 7.06 (d, 2H), 7.01 (d, 1H), 6.72(dd, 1H), 6.65 (m, 1H), 6.49 (dd, 1H), 6.41 (m, 2H), 3.93 (dd, 2H), 3.77(br s, 2H), 3.30 (m, 2H), 3.10 (m, 6H), 2.77 (s, 2H), 2.69 (m, 2H), 2.24(m, 4H), 2.18 (t, 2H), 2.06 (d, 2H), 1.98 (s, 2H), 1.80 (d, 2H), 1.68(m, 2H), 1.52 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1144-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.74 (br m, 1H), 8.43 (d, 1H), 7.73 (dd, 1H),7.52 (d, 1H), 7.35 (m, 2H), 7.19 (m, 1H), 7.06 (m, 3H), 6.73 (m, 2H),6.50 (m, 2H), 6.44 (d, 1H), 3.64 (t, 4H), 3.45 (m, 2H), 3.18 (m, 5H),2.79 (m, 2H), 2.58 (m, 3H), 2.22 (m, 7H), 1.98 (m, 3H), 1.83 (m, 2H),1.41 (m, 2H), 0.94 (s, 6H).

EXAMPLE 1152-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.33 (d, 1H), 8.09 (s, 1H), 7.70 (d, 1H), 7.63(d, 1H), 7.34 (m, 3H), 7.03 (m, 4H), 6.87 (t, 1H), 6.69 (m, 1H), 6.50(d, 1H), 6.25 (d, 1H), 3.91 (d, 2H), 3.57 (s, 4H), 3.30 (m, 6H), 3.06(s, 4H), 2.20 (d, 6H), 1.96 (d, 4H), 1.73 (s, 2H), 1.63 (s, 2H), 1.48(s, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1162-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.70 (t, 1H), 8.44 (d, 1H), 7.77 (dd, 1H), 7.54(d, 1H), 7.40 (dd, 1H), 7.35 (m, 2H), 7.12 (m, 1H), 7.06 (m, 3H), 6.98(td, 1H), 6.73 (dd, 1H), 6.68 (dd, 1H), 6.26 (d, 1H), 4.62 (s, 2H), 3.62(m, 4H), 3.46 (dd, 2H), 3.11 (s, 4H), 2.75 (d, 2H), 2.47 (m, 4H), 2.20(d, 6H), 1.97 (s, 2H), 1.82 (p, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1172-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 117A4-(1-cyclopentylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting1-cyclopentylpiperidin-4-amine for 3-(N-morpholinyl)-1-propylamine inEXAMPLE 4A.

EXAMPLE 117B2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE1F and EXAMPLE 117A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.35 (d, 1H), 8.06 (d, 1H), 7.73 (dd, 1H), 7.63(d, 1H), 7.35 (m, 3H), 7.04 (m, 4H), 6.88 (td, 1H), 6.69 (dd, 1H), 6.53(dd, 1H), 6.25 (d, 1H), 4.57 (s, 1H), 3.29 (s, 8H), 3.05 (d, 4H), 2.75(s, 2H), 2.62 (s, 2H), 2.20 (d, 5H), 2.07 (s, 1H), 1.95 (d, 3H), 1.66(s, 3H), 1.53 (s, 3H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1184-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(4-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 118A ethyl 4-fluoro-2-(4-fluorophenoxy)benzoate

The title compound was prepared by substituting 4-fluorophenol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 118B ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yi)-2-(4-fluorophenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 118A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 118C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(4-fluorophenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 118B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 118D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(4-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 118C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.39 (d, 1H), 8.08 (d, 1H), 7.75 (dd, 1H), 7.55(d, 1H), 7.36 (d, 2H), 7.06 (m, 3H), 6.98 (m, 2H), 6.73 (m, 2H), 6.07(dd, 1H), 6.29 (d, 1H), 3.82 (m, 1H), 3.18 (m, 2H), 3.08 (m, 4H), 2.80(m, 4H), 2.60 (m, 3H), 2.22 (m, 6H), 2.07 (m, 2H), 1.97 (m, 2H), 1.77(m, 2H), 1.40 (m, 2H), 0.94 (s, 6H).

EXAMPLE 1192-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 36C and EXAMPLE 65A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.35 (d, 1H),8.17 (d, 1H), 7.66 (dd, 1H), 7.58 (d, 1H), 7.36 (d, 2H), 7.15 (t, 1H),7.05 (m, 3H), 6.88 (d, 1H), 6.74 (dd, 1H), 6.64 (m, 2H), 6.41 (d, 1H),3.69 (m, 1H), 3.16 (m, 4H), 2.97 (m,4H), 2.77 (m, 2H), 2.72 (s, 2H),2.44 (m, 3H), 2.21 (m, 3H), 1.96 (m, 2H), 1.58 (m, 3H), 0.94 (s, 6H),0.40 (m, 5H).

EXAMPLE 1202-(2-chloro-4-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 61D for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.73 (m, 1H), 8.48 (d, 1H), 7.80 (dd, 1H), 7.51(d, 1H), 7.36 (m, 3H), 7.07 (m, 4H), 6.75 (m, 2H), 6.25 (d, 1H), 3.63(m, 4H), 3.47 (m, 2H), 3.12 (m, 4H), 2.77 (s, 2H), 2.21 (m, 6H), 1.97(s, 2H), 1.82 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1214-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2,3-difluorophenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE1F and EXAMPLE 65A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.42 (d, 1H), 8.21 (d, 1H), 7.77 (dd, 1H), 7.54(d, 1H), 7.35 (d, 2H), 7.15 (d, 1H), 7.06 (d, 2H), 6.89 (m, 2H), 6.75(dd, 1H), 6.44 (m, 2H), 3.76 (m, 1H), 3.17 (m, 4H), 3.00 (m, 2H), 2.81(s, 2H), 2.59 (m, 2H), 2.24 (m, 6H), 1.92 (m, 5H), 1.61 (m, 2H), 1.41(t, 2H), 0.94 (s, 6H), 0.46 (m, 4H).

EXAMPLE 1224-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 122A methyl 4-fluoro-2-(2-fluorophenoxy)benzoate

The title compound was prepared by substituting 2-fluorophenol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 122B methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(2-fluorophenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 122A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 122C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(2-fluorophenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 122B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 122D

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 122C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.87 (s, 1H), 9.54 (s, 1H), 8.50 (d, 1H), 8.20(d, 1H), 7.86 (dd, 1H), 7.52 (d, 1H), 7.40 (d, 2H), 7.24 (m, 2H), 7.10(d, 2H), 7.03 (m, 2H), 6.78 (m, 2H), 6.42 (s, 1H), 3.62 (m, 10H), 3.10(m, 4H), 2.82 (m, 2H), 2.82 (s, 3H), 2.21 (m, 4H), 2.03 (s, 2H), 1.85(m, 1H), 1.46 (t, 2H), 0.96 (s, 6H).

EXAMPLE 1234-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2-fluorophenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 122C for EXAMPLE1F and EXAMPLE 65A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.51 (d, 1H), 8.19 (s, 1H), 7.87 (dd, 1H), 7.53(d, 1H), 7.40 (d, 2H), 7.24 (m, 2H), 7.11 (d, 2H), 7.03 (m, 2H), 6.78(m, 2H), 6.43 (d, 1H), 3.97 (m, 4H), 3.21 (s, 8H), 3.21 (s, 4H), 2.83(m, 4H), 2.22 (m, 4H), 2.06 (m, 2H), 1.81 (m, 1H), 1.47 (t, 2H), 0.96(s, 6H).

EXAMPLE 1244-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 122C for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.90 (s, 1H), 9.59 (s, 1H), 8.51 (m, 1H), 8.20(d, 1H), 7.87 (dd, 1H), 7.53 (d, 1H), 7.39 (d, 2H), 7.24 (m, 2H), 7.10(d, 2H), 7.03 (m, 2H), 6.78 (m, 2H), 6.42 (s, 1H), 4.01 (m, 2H), 3.71(m, 4H), 3.34 (m, 6H), 3.17 (m, 4H), 2.78 (m, 2H), 2.24 (m, 4H), 1.94(m, 8H), 1.70 (m, 2H), 1.46 (t, 2H), 0.96 (s, 6H).

EXAMPLE 1254-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 122C for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.85 (s, 1H), 9.94 (s, 1H), 9.63 (s, 1H), 8.71(m, 1H), 8.53 (d, 1H), 7.86 (dd, 1H), 7.53 (d, 1H), 7.40 (d, 2H), 7.26(m, 1H), 7.19 (d, 1H), 7.07 (m, 4H), 6.80 (m, 2H), 6.41 (d, 1H), 3.97(m, 2H), 3.54 (m, 6H), 3.31 (m, 4H), 3.19 (m, 8H), 2.22 (m, 2H), 1.99(m, 4H), 1.47 (t, 2H), 0.97 (s, 6H).

EXAMPLE 1264-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 126A 4-(2-morpholinoethylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting2-(N-morpholinyl)-2-ethylamine for 3-(N-morpholinyl)-1-propylamine inEXAMPLE 4A.

EXAMPLE 126B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 122C for EXAMPLE1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.81 (s, 1H), 8.50 (d, 1H), 7.82 (dd, 1H), 7.50(d, 1H), 7.36 (d, 2H), 7.23 (m, 1H), 7.04 (m, 5H), 6.79 (m, 1H), 6.73(dd, 1H), 6.31 (d, 1H), 3.62 (m, 4H), 3.50 (q, 2H), 3.32 (m, 6H), 3.14(m, 4H), 2.79 (s, 2H), 2.67 (m, 2H), 2.20 (m, 6H), 1.99 (m, 2H), 1.40(t, 2H), 0.94 (s, 6H).

EXAMPLE 1272-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G is EXAMPLE 1 H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.38 (m, 1H), 8.13 (m, 1H), 7.70 (m, 1H), 7.59(m, 1H), 7.36 (d, 2H), 7.16 (m, 1H), 7.05 (m, 3H), 6.89 (m, 1H), 6.74(dd, 1H), 6.66 (dd, 1H), 6.61 (m, 1H), 6.42 (m, 1H), 3.94 (m, 2H), 3.26(m, 6H), 3.15 (m, 6H), 2.78 (m, 2H), 2.18 (m, 9 H), 1.98 (m, 3H), 1.86(m, 2H), 1.74 (m, 2H), 1.57 (m, 2H), 1.41 (m, 2H), 0.93 (s, 6H).

EXAMPLE 1282-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.75 (t, 1H), 8.41 (d, 1H), 7.71 (dd, 1H), 7.52(d, 1H), 7.36 (d, 2H), 7.18 (m, 1H), 7.06 (m, 3H), 6.93 (dd, 1H), 6.77(dd, 1H), 6.69 (m, 2H), 6.46 (d, 1H), 3.65 (t, 4H), 3.47 (q, 2H), 3.29(m, 2H), 3.18 (m, 4H), 2.79 (s, 2H), 2.56 (m, 4H), 2.22 (m, 6H), 1.98(m, 2H), 1.85 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1294-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.48 (a, 1H), 8.81 (t, 1H), 8.45 (d, 1H), 7.75(dd, 1H), 7.49 (d, 1H), 7.36 (d, 2H), 7.19 (m, 1H), 7.06 (m, 3H), 6.77(dd, 1H), 6.72 (m, 1H), 6.54 (m, 2H), 6.47 (d, 1H), 3.62 (m, 4H), 3.50(q, 2H), 3.32 (m, 4H), 3.19 (m, 4H), 2.82 (s, 2H), 2.69 (t, 2H), 2.27(m, 4H), 2.18 (s, 2H), 1.99 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1302-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 117A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.35 (d, 1H), 8.08 (d, 1H), 7.69 (dd1H), 7.61(d, 1H), 7.3 S(d, 2H), 7.14 (m, 1H), 7.04 (m, 3H), 6.88 (dd, 1H), 6.72(dd, 1H), 6.65 (dd, 1H), 6.60 (m, 1H), 6.39 (d, 1H), 3.87 (s, 1H), 3.11(m, 6H), 2.93 (m, 2H), 2.77 (s, 2H), 2.21 (m, 8H), 1.98 (m, 5H), 1.69(m, 4H), 1.56 (m, 4H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1312-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideEXAMPLE 131A (2-fluorophenyl)(trifluoromethyl)sulfane

Methyl viologen hydrochloride (1.17 g) in N,N-dimethylformamide (80 mL)at 25° C. was saturated with trifluoromethyl iodide, treated wih2-fluorobenzenethiol (9.7 mL) and triethylamine (20 mL), stirred for 24hours, diluted with water (240 mL) and extracted with diethyl ether. Theextract was washed with 1M aqueous NaOH, saturated ammonium chloride andbrine and concentrated.

EXAMPLE 131B 1-fluoro-2-(trifluoromethylsulfonyl)benzene

EXAMPLE 131A (17.346 g) in 1:1:2 carbon tetrachloride:acetonitrile:water(800 mL) at 25° C. was treated with sodium periodate (56.8 g) andruthenium(III) chloride hydrate (183 mg), stirred for 18 hours, dilutedwith dichloromethane (100 mL) and filtered through diatomaceous earth(Celite®). The filtrate was washed with saturated sodium bicarbonate andextracted with dichloromethane. The extract was washed with brine anddried (MgSO₄), filtered and concentrated. The concentrate was filteredthrough silica gel.

EXAMPLE 131C 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide

EXAMPLE 131B (37.3 g) in chlorosulfonic acid (32.8 mL) at 120° C. wasstirred for 18 hours, cooled to 25° C. and pipetted onto crushed ice.The mixture was extracted with ethyl acetate, and the extract was washedwith water and brine and dried (MgSO₄), filtered and concentrated. Thecrude product was taken up in isopropanol (706 mL) at −78° C., treatedwith ammonium hydroxide (98 mL) over 1 hour, stirred for 1 hour,quenched with 6M aqueous HCl (353 mL), warmed to 25° C. andconcentrated. The concentrate was mixed with water and extracted withethyl acetate. The extract was dried over MgSO₄, filtered andconcentrated. The concentrate was recrystallized from ethylacetate/hexane.

EXAMPLE 131D

4-(1-methylpiperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzensulfonamide

The title compound was prepared by substituting1-methyl-4-aminopiperidine for 3-(N-morpholinyl)-1-propylamine andEXAMPLE 131C for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 4A.

EXAMPLE 131E2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 131D for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.00 (d, 1H), 7.83 (dd, 1H), 7.61 (d, 1H), 7.36(m, 2H), 7.19 (m, 1H), 7.07 (d, 2H), 7.01 (d, 1H), 6.93 (d, 1H), 6.72(dd, 1H), 6.66 (m, 2H), 6.51 (d, 1H), 6.39 (d, 1H), 3.79 (none, 1H),3.11 (m, 6H), 2.90 (t, 2H), 2.78 (s, 2H), 2.65 (s, 3H), 2.20 (m, 6H),2.09 (m, 2H), 1.97 (m, 3H), 1.64 (m, 2H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 1324-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(3-fluorophenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE1F and EXAMPLE 65A for EXAMPLE 1G is EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.43 (d, 1H), 8.23 (d, 1H), 7.75 (dd, 1H), 7.51(d, 1H), 7.35 (d, 2H), 7.17 (m, 2H), 7.06 (d, 2H), 6.73 (m, 2H), 6.56(dd, 1H), 6.51 (dd, 1H), 6.45 (d, 1H), 3.74 (m, 1H), 3.18 (m, 4H), 2.97(m, 2H), 2.80 (s, 2H), 2.54 (m, 2H), 2.20 (m, 6H), 1.98 (m, 4H), 1.85(m, 1H), 1.62 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H), 0.50 (m, 2H), 0.41(m, 2H).

EXAMPLE 1334-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2,3-difluorophenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE1F and EXAMPLE 117A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.35 (d, 1H), 8.05 (s, 1H), 7.73 (dd, 1H), 7.64(d, 1H), 7.36 (d, 2H), 7.06 (m, 3H), 6.84 (m, 2H), 6.72 (dd, 1H), 6.43(d, 1H), 6.31 (m, 1H), 3.89 (s, 1H), 3.12 (m, 6H), 2.97 (m, 2H), 2.77(s, 2H), 2.21 (m, 8H), 1.98 (m, 5H), 1.63 (m, 8H), 1.41 (t, 2H), 0.95(s, 6H).

EXAMPLE 1344-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(2-fluorophenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 122C for EXAMPLE1F and EXAMPLE 117A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.39 (m, 1H), 8.07 (d, 1H), 7.76 (m, 1H), 7.61(d, 1H), 7.34 (d, 2H), 7.18 (m,2H), 7.07 (m, 3H), 6.91 (m, 2H), 6.68 (m,1H), 6.28 (m, 1H), 3.26 (m, 8H), 3.17 (m, 2H), 3.05 (m, 4H), 2.75 (s,2H), 2.23 (m, 7H), 2.00 (m, 4H), 1.64 (m, 6H), 1.40 (m, 2H), 0.94 (s,6H).

EXAMPLE 1354-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.77 (m, 1H), 8.45 (d, 1H), 7.78 (dd, 1H), 7.52(d, 1H), 7.34 (d, 2H), 7.06 (m, 3H), 6.91 (m, 2H), 6.76 (dd, 1H), 6.45(m, 2H), 3.62 (m, 4H), 3.49 (m, 2H), 3.18 (m, 4H), 2.81 (s, 2H), 2.68(t, 2H), 2.23 (m, 6H), 1.97 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1364-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(3-nitro-4-{[1-(thien-3-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamideEXAMPLE 136A 4-(2-Nitro-4-sulfamoyl-phenylamino)-piperidine-1-carboxylicacid tert-butyl ester

Tert-butyl-4-aminopiperidine-1-carboxylate (8.63 g) was dissolved in1,4-dioxane (250 mL), and 4-chloro-3-nitrobenzenesulfonamide (6.00 g)was added followed by triethylamine (10.60 mL). The solution was heatedat 90° C. for 20 hours and then cooled. The solvent was removed undervacuum, and the material was purified by flash column chromatography onsilica gel using 50% ethyl acetate in hexanes, increasing to 100% ethylacetate and increasing further to 20% methanol in dichloromethane.

EXAMPLE 136B 3-Nitro-4-(piperidin-4-ylamino)-benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 136A for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 136C3-nitro-4-(1-(thiophen-3-ylmethyl)piperidin-4-ylamino)benzenesulfonamide

The title compound was prepared by substituting thiophene-3-carbaldehydefor 4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 136B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 136D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(3-nitro-4-{[1-(thien-3-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE1F and EXAMPLE 136C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.39 (d, 1H), 8.16 (d, 1H), 7.74 (dd, 1H), 7.54(m, 3H), 7.35 (d, 2H), 7.10 (m, 4H), 6.87 (m, 2H), 6.74 (dd, 1H), 6.40(m, 2H), 3.84 (m, 3H), 3.15 (m, 4H), 3.03 (m, 2H), 2.79 (s, 2H), 2.62(m, 2H), 2.23 (m, 6H), 2.02 (m, 4H), 1.73 (m, 2H), 1.41 (t, 2H), 0.94(s, 6H).

EXAMPLE 1374-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-fluorophenoxy)benzamide

EXAMPLE 122C (203 mg), EXAMPLE 11A (124 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (142 mg),and 4-dimethylaminopyridine (90 mg) were stirred in CH₂Cl₂ (8 mL)overnight. The reaction was concentrated and the crude was purified bypreparative HPLC using a C18 column, 250×50 mm, 10μ, and eluting with agradient of 20-100% CH₃CN vs. 0.1% trifluoroacetic acid in water, givingthe product as a trifluoroacetate salt. The salt was dissolved indichloromethane (6 mL) and washed with 50% aqueous NaHCO₃. The organiclayer was dried over anhydrous Na₂SO₄, filtered, and concentrated togive the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.71(br t, 1H), 8.38 (d, 1H), 7.75 (dd, 1H), 7.63 (d, 1H), 7.37 (d, 2H),7.18 (m, 1H), 7.06 (d, 2H), 6.98 (d, 1H), 6.92 (m, 2H), 6.66 (dd, 1H),6.60 (m, 1H), 6.26 (d, 1H), 3.47 (dd, 2H), 3.05 (br m, 4H), 2.89 (br m,2H), 2.75 (s, 2H), 2.60 (s, 6H), 2.20 (br m, 6H), 1.98 (s, 2H), 1.88 (m,2H), 1.40 (t, 2H), 0.93 (s, 6H).

EXAMPLE 1384-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-fluorophenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE122C in EXAMPLE 137. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.70 (brt, 1H), 8.35 (d, 1H), 7.69 (dd, 1H), 7.62 (d, 1H), 7.37 (d, 2H), 7.15(dd, 1H), 7.06 (d, 2H), 6.95 (d, 1H), 6.70 (m, 2H), 6.50 (dd, 1H), 6.41(m, 1H), 6.38 (d, 1H), 3.47 (dd, 2H), 3.10 (br m, 4H), 2.94 (br m, 2H),2.78 (s, 2H), 2.62 (s, 6H), 2.23 (br m, 6H),1.99 (s, 2H), 1.90 (m, 2H)1.40 (t, 2H), 0.93 (s, 6H).

EXAMPLE 1394-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(4-fluorophenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 118C for EXAMPLE122C is EXAMPLE 137. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.75 (brt, 1H), 8.39 (d, 1H), 7.75 (dd, 1H), 7.58 (d, 1H), 7.37 (d, 2H), 7.06(d, 2H), 7.00 (m, 3H), 6.75 (m,2H), 6.66 (dd, 1H), 6.28 (d, 1H), 3.47(dd, 2H), 3.05 (br m, 4H), 2.89 (br m, 2H), 2.75 (s, 2H), 2.60 (s, 6H),2.20 (br m, 6H), 1.98 (s, 2H), 1.88 (m, 2H) 1.40 (t, 2H), 0.93 (s, 6H).

EXAMPLE 1404-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-(2-fluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 140A 4-(2-Nitro-4-sulfamoyl-phenylamino)-piperidine-1-carboxylicacid tert-butyl ester

Tert-butyl 4-aminopiperidine-1-carboxylate (8.63 g) was dissolved in1,4-dioxane (250 mL), and 4-chloro-3-nitrobenzenesulfonamide (6.00 g)was added followed by triethylamin (10.60 mL). The solution was heatedat 90° C. for 20 hours and then cooled. The solvent was removed undervacuum, and the material purified by flash column chromatography onsilica gel using 50% ethyl acetate in hexanes, increasing to 100% ethylacetate and increasing further to 20% methanol in dichloromethane.

EXAMPLE 140B

3-Nitro-4-(piperidin-4-ylamino)-benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 140A for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 140C4-[1-(2-Fluoro-ethyl)-piperidin-4-ylamino]-3-nitro-benzenesulfonamide

To EXAMPLE 140B (1000 mg) was added N,N-dimethylformamide (10 mL).1-Fluoro-2-iodoethane (462 mg) and triethylamine (1.18 mL) were addedand the solution was heated at 70° C. for 16 hours. The solvent wasremoved under vacuum, and the mateiral purified by flash columnchromatography on silica gel using ethyl acetate increasing to 10%methanol in dichloromethane.

EXAMPLE 140D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-(2-fluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE1F and EXAMPLE 140C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.41 (d, 1H), 8.21 (d, 1H), 7.76 (dd, 1H), 7.56(d, 1H), 7.37 (d, 2H), 7.14 (d, 1H), 7.07 (d, 2H), 6.94-6.82 (m, 2H),6.76 (dd, 1H), 6.48 (d, 1H), 6.41-6.34 (m, 1H), 4.71 (t, 1H), 4.55 (t,1H), 3.89-3.70 (m, 2H), 3.17 (br s, 4H), 3.09-2.90 (m, 4H), 2.91-2.77(m, 3H), 2.26 (br s, 4H), 2.18 (m, 2H), 2.08-1.96 (m, 4H), 1.71 (q, 2H),1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 1412-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.81 (t, 1H), 8.44 (d, 1H), 7.73 (dd, 1H), 7.51(d, 1H), 7.36 (d, 2H), 7.18 (t, 1H), 7.07 (d, 2H), 7.04 (d, 1H), 6.93(dt, 1H), 6.78 (dd, 1H), 6.71 (dd, 1H), 6.69 (d, 1H), 6.47 (d, 1H), 3.62(t, 4H), 3.50 (q, 2H), 3.20 (br s, 4H), 2.81 (br s, 2H), 2.69 (t, 2H),2.26 (m, 4H), 2.18 (t, 2H), 2.02-1.93 (m, 4H), 1.41 (t, 2H), 1.37-1.22(m, 2H), 0.95 (s, 6H).

EXAMPLE 1422-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE122C in EXAMPLE 137. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.71 (brt, 1H), 8.34 (d, 1H), 7.65 (dd, 1H), 7.63 (d, 1H), 7.37 (d, 2H), 7.16(dd, 1H), 7.07 (d, 2H), 6.93 (d, 1H), 6.89 (m, 1H), 6.73 (dd, 1H), 6.64(dd, 1H), 6.60 (dd, 1H), 6.38 (d, 1H), 3.45 (dd, 2H), 3.09 (br m, 4H),2.93 (br m, 2H), 2.78 (s, 2H), 2.62 (s, 6H), 2.23 (br m, 6H), 1.98 (s,2H), 1.90 (m, 2H), 1.41 (t, 2H), 0.93 (s, 6H).

EXAMPLE 1432-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 143A4-[3-(4-Methyl-piperazin-1-yl)-propylamino]-3-nitro-benzenesulfonamide

The title compound was prepared by substituting1-(3-aminopropyl)-4-methylpiperazine for tert-butyl4-aminopiperidine-1-carboxylate is EXAMPLE 140A.

EXAMPLE 143B2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 143A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.55 (t, 1H), 8.39 (d, 1H), 7.67 (dd, 1H), 7.61(d, 1H), 7.36 (d, 2H), 7.15 (t, 1H), 7.07 (d, 2H), 6.95 (d, 1H), 6.89(dd, 1H), 6.73 (dd, 1H), 6.65 (d, 1H), 6.60 (t, 1H), 6.40 (d, 1H), 3.43(q, 2H), 3.12 (br s, 4H), 2.89 (br s, 2H), 2.77 (s, 2H), 2.60-2.45 (m,9H), 2.29-2.15 (m, 8H), 1.98 (br s, 2H), 1.81 (m, 2H), 1.41 (t, 2H),0.94 (s, 6H).

EXAMPLE 1442-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 144A methyl 2-(3-chlorophenoxy)-4-(piperazin-1-yl)benzoate

This example was prepared by substituting piperazine for EXAMPLE 3E andEXAMPLE 36A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 144B methyl2-(3-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 144A for EXAMPLE 38Fin EXAMPLE 38G.

EXAMPLE 144C2-(3-chlorophenoxy)-4-(4-((4(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 38 H byreplacing EXAMPLE 38G with EXAMPLE 144B.

EXAMPLE 144D2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 144C and EXAMPLE 3I,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.33 (d, 1H),8.07 (d, 1H), 7.68 (dd, 1H), 7.62 (d, 1H), 7.40 (d, 2H), 7.15 (m, 3H),7.01 (d, 1H), 6.86 (m, 1H), 6.72 (m, 1H), 6.64 (dd, 1H), 6.58 (m, 1H),6.39 (d, 1H), 4.15 (s, 2H), 3.83 (m, 1H), 3.17 (m, 8H), 2.87 (s, 3H),2.63 (m, 5H), 2.26 (m, 4H), 2.13 (m, 3H), 1.79 (m, 1H), 1.20 (s, 6H).

EXAMPLE 1454-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(1methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 145A methyl 2-(2,3-difluorophenoxy)-4-(piperazin-1-yl)benzoate

This exmple was prepared for substituting piperazine for EXAMPLE 3F andEXAMPLE 45A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 145B methyl2-(2,3-difluorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 145A for EXAMPLE 38Fin EXAMPLE 38G.

EXAMPLE 145C

4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 38H by replacingEXAMPLE 38G with EXAMPLE 145B.

EXAMPLE 145D4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(1methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 145C and EXAMPLE 3I,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.32 (d, 1H),8.06 (d, 1H), 7.71 (dd, 1H), 7.66 (d, 1H), 7.40 (d, 2H), 7.15 (s, 2H),7.03 (d, 1H), 6.81 (m, 2H), 6.73 (m, 1H), 6.43 (m, 1H), 6.27 (m, 1H),4.15 (m, 2H), 3.83 (m, 1H), 3.16 (m, 8H), 2.88 (s, 3H), 2.70 (m, 4H),2.26 (s, 4H), 2.13 (m, 4H), 1.78 (m, 1H), 1.21 (s, 6H).

EXAMPLE 146N-({4-[(1-allylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)benzamideEXAMPLE 146A 4-(1-allylpiperidin-4-ylamin)-3-nitrobenzenesulfonamide

3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide hydrochloride (0.27g), triethylamine (0.2 mL) and 3-bromoprop-1-ene (0.1 g) was dissolvedin N,N-dimethylformamide (5 mL). The mixture was stirred at roomtemperature overnight. The solvent was dried under vacuum. The mixturewas chromatographed on silica gel with 0-20% methanol indichloromethane.

EXAMPLE 146BN-({4-[(1-allylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)benzamide

The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE1F and EXAMPLE 146A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.39 (d, 1H), 8.14 (d, 1H), 7.75 (dd, 1H), 7.59(d, 1H), 7.35 (d, 2H), 7.08 (m, 3H), 6.86 (m, 2H), 6.74 (dd, 1H), 6.45(d, 1H), 6.36 (m, 1H), 5.88 (m, 1H), 5.37 (m, 2H), 3.83 (m, 1H), 3.13(m, 8H), 2.74 (m, 4H), 2.17 (m, 8H), 1.98 (s, 2H), 1.74 (m, 2H), 1.41(t, 2H), 0.94 (s, 6H).

EXAMPLE 1472-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 147A methyl 2-(3-chloro-2-fluorophenoxy)-4-fluorobenzoate

The title compound was prepared by substituting 3-chloro-2-fluorophenolfor 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 147B Ethyl2-(3-chloro-2-fluorophenoxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared by substituting piperazine for EXAMPLE3F and EXAMPLE 147A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 147C Ethyl2-(3-chloro-2-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 60D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 147B fortert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 147D2-(3-chloro-2-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 147C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 147E2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 147D for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.33 (d, 1H), 8.05 (d, 1H), 7.68 (m, 2H), 7.35(d, 2H), 7.02 (m, 4H), 6.84 (m, 1H), 6.72 (d, 1H), 6.43 (m, 2H), 3.83(m, 1H), 3.12 (m, 6H), 2.84 (m, 4H), 2.62 (s, 3H), 2.22 (m, 6H), 2.11(m, 2H), 1.98 (s, 2H), 1.76 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1482-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 147D for EXAMPLE1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1 H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.71 (m, 1H), 8.41 (d, 1H), 7.74 (dd, 1H), 7.56(d, 1H), 7.35 (d, 2H), 7.05 (m, 4H), 6.91 (m, 1H), 6.75 (dd, 1H), 6.56(m, 1H), 6.47 (d, 1H), 3.64 (m, 4H), 3.47 (q, 2H), 3.17 (m, 4H), 2.79(s, 2H) 2.55 (m, 6H), 2.22 (m, 6H), 1.98 (s, 2H), 1.84 (m, 2H), 1.41 (t,2H), 0.95 (s, 6H).

EXAMPLE 1492-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 149A3-nitro-4-(3-(pyrrolidin-1-yl)propylamino)benzenesulfonamide

The title compound was prepared by substituting3-(pyrrolidin-1-yl)propan-1-amine for 3-(N-morpholinyl)-1-propylamine inEXAMPLE 4A.

EXAMPLE 149B2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 147D for EXAMPLE1F and EXAMPLE 149A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.43 (s, 1H), 8.32 (d, 1H), 7.70 (m, 2H), 7.35(d, 2H), 7.07 (d, 2H), 6.97 (m, 2H), 6.85 (m, 1H), 6.71 (dd, 1H), 6.43(m, 2H), 3.48 (q, 2H), 3.09 (m, 8H), 2.77 (s, 2H), 2.21 (m, 8H), 1.92(m, 8H), 1,40 (t, 2H), 0, 94 (s, 6H).

EXAMPLE 1502-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 147D for EXAMPLE1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.79 (m, 1H), 8.44 (d, 1H), 7.76 (dd, 1H), 7.53(d, 1H), 7.36 (d, 2H), 7.06 (m, 4H), 6.91 (m, 1H), 6.76 (dd, 1H), 6.58(m, 1H), 6.48 (d, 1H), 3.62 (m, 4H), 3.50 (q, 2H), 3.19 (m, 4H), 2.81(s, 2H), 2.69 (m, 2H), 2.23 (m, 6H), 1.98 (s, 2H), 1.41 (t, 2H), 0.94(s, 6H).

EXAMPLE 1512-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 151A methyl 2-(2-chloro-6-fluorophenoxy)-4-fluorobenzoate

The title compound was prepared by substituting 2-chloro-6-fluorophenolfor 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 151B methyl2-(2-chloro-6-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 151A for EXAMPLE153A in EXAMPLE 3G.

EXAMPLE 151C2-(2-chloro-6-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 151B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 151D2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 151C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.51 (d, 1H), 8.09 (d, 1H), 7.92 (dd, 1H), 7.60(d, 1H), 7.32 (m, 5H), 7.17 (d, 1H), 7.05 (d, 2H), 6.56 (dd, 1H), 5.83(d, 1H), 3.85 (m, 1H), 3.17 (m, 2H), 2.95 (m, 4H), 2.81 (m, 2H), 2.73(s, 2H), 2.59 (s, 3H), 2.15 (m, 8H), 1.97 (m, 2H), 1.77 (m, 2H), 1.39(t, 2H), 0.93 (s, 6H).

EXAMPLE 1522-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 151C for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 10 in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.54 (d, 1H), 8.14 (d, 1H), 7.93 (dd, 1H), 7.58(d, 1H), 7.34 (m, 5H), 7.20 (d, 1H), 7.04 (d, 2H), 6.59 (dd, 1H), 5.85(d, 1H), 3.93 (dd, 2H), 3.85 (m, 1H), 3.21 (s, 6H), 2.97 (m, 4H), 2.73(m, 4H), 2.16 (m, 8H), 1.96 (s, 2H), 1.81 (m, 2H), 1.69 (m, 2H), 1.54(m, 2H), 1.39 (t, 214), 0.93 (s, 6H).

EXAMPLE 1544-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 154A 6-fluoro-1H-indol-5-ol

The title compound was prepared from 2-fluoro-4-nitrophenol according toWO 02/12227 (page 78).

EXAMPLE 154B methyl 4-fluoro-2-(6-ftuoro-1H-indol-5-yloxy)benzoate

The title compound was prepared as described in EXAMPLE 3A by replacing2-methyl-5-indolol with EXAMPLE 154A.

EXAMPLE 154C methyl2-(6-fluoro-1H-indol-5-yloxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared as describedin EXAMPLE 3G by replacingEXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE 154B,respectively.

EXAMPLE 154D methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoate

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLE 38F and EXAMPLE 38E with EXAMPLE 154C and EXAMPLE 60D,respectively.

EXAMPLE 154E4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoicacid

The title compound was prepared as described in EXAMPLE 38 H byreplacing EXAMPLE 38G with EXAMPLE 154D.

EXAMPLE 154F4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 154E and EXAMPLE 31,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.12 (m, 1H),8.49 (d, 1H), 8.11 (d, 1H), 7.82 (dd, 1H), 7.55 (d, 1H), 7.33 (m, 3H),7.28 (d, 1H), 7.11 (d, 1H), 7.05 (m, 2H), 6.59 (dd, 1H), 6.35 (m, 1H),6.08 (m, 1H), 3.76 (m, 1H), 3.06 (m, 8H), 2.72 (m, 6H), 2.17 (s, 6H),1.98 (m, 5H), 1.72 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 1552-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 155A4-((1-methylpiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting4-aminomethyl-N-methylpiperidine for 3-(N-morpholinyl-1-propylamine inEXAMPLE 4A.

EXAMPLE 155B2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 155A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.45 (br t, 1H), 8.33 (d, 1H), 7.65 (m, 2H),7.36 (d, 2H), 7.15 (t, 1H), 7.06 (d, 2H), 6.97 (d, 1H), 6.89 (d, 1H),6.60 (m, 2H), 6.38 (d, 1H), 3.02-3.12 (m, 8H), 2.77 (m, 4H), 2.65 (m,2H), 2.24 (m, 4H), 2.19 (m, 2H), 1.91 (m, 1H), 1.87 (m, 2H), 1.41 (m,4H), 0.95 (s, 6H).

EXAMPLE 1564-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE1F and EXAMPLE 155A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.54 (br t, 1H), 8.37 (d, 1H), 7.72 (d, 1H),7.60 (d, 1H), 7.36 (d, 2H), 7.07 (d, 3H), 6.88 (dd, 2H), 6.75 (d, 1H),6.46 (s, 1H), 6.36 (br s, 1H), 3.16 (m, 8H), 2.89 (m, 2H), 2.81 (m, 2H),2.68 (s, 3H), 2.27 (m, 4H), 2.20 (m, 2H), 1.99 (m, 2H), 1.91 (m, 3H),1.55 (m, 2H), 1.41 (m, 2H), 0.95 (s, 6H).

EXAMPLE 1574-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(4-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 157A 4-fluoro-1H-indol-5-ol

The title compound was prepared from 2-fluoro-4-nitrophenol according toWO 02 12227 (page 78).

EXAMPLE 157B methyl 4-fluoro-2-(4-fluoro-1H-indol-5-yloxy)benzoate

The title compound was prepared as described in EXAMPLE 3A by replacing2-methyl-5-indolol with EXAMPLE 157A.

EXAMPLE 157C methyl2-(4-fluoro-1H-indol-5-yloxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 3G by replacingEXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE 157B respectively.

EXAMPLE 157D methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(4-fluoro)-1H-indol-5-yloxy)benzoate

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLE 38F and EXAMPLE 38E with EXAMPLE 157C and EXAMPLE 60D,respectively.

EXAMPLE 157E4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(4-fluoro-1H-indol-5-yloxy)benzoicacid

The title compound was prepared as described in EXAMPLE 38 H byreplacing EXAMPLE 38G with EXAMPLE 157D.

EXAMPLE 157F4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(4-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1E and EXAMPLE 1G with EXAMPLE 157E and EXAMPLE 31. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.40 (m, 1H), 8.53 (d, 1H), 8.12 (d, 1H),7.88 (d, 1H), 7.53 (d, 1H), 7.42 (t, 1H), 7.33 (d, 2H), 7.16 (dd, 2H),7.05 (d, 2H), 6.83 (m, 1H), 6.52 (m, 2H), 6.02 (s, 1H), 3.77 (m, 2H),3.03 (m, 6H), 2.70 (s, 3H), 2.04 (m, 12H), 1.71 (m, 2H), 0.92 (s, 6H).

EXAMPLE 1584-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[3-(methoxymethoxy)-2-methylphenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 158A Ethyl 4-fluoro-2-(3-hydroxy-2-methylphenoxy)benzoate

The title compound was prepared by substituting 2-methylbenzene-1,3-diolfor 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 158B ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-hydroxy-2-methylphenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 158A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 158C Ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-(methoxymethoxy)-2-methylphenoxy)benzoate

A mixture of EXAMPLE 158B (0.6 g), chloro(methoxy)methane (0.18 g) andcesium carbonate (0.9 g) was suspended in N,N-dimethylformamide (15 mL).After it stirred at room temperature for 30 minutes, the crude productwas purified by preparative HPLC using a 250×50 mm C18 column andeluting with 20-100% CH₃CN vs 0.1% trifluoroacetic acid in water.

EXAMPLE 158D4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-(methoxymethoxy)-2-methylphenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 158C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 158E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-hydroxy-2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 158D for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.43 (d, 1H), 8.10 (d, 1H), 7.73 (dd, 1H), 7.54(d, 1H), 7.35 (d, 2H), 7.07 (m, 3H), 6.94 (t, 1H), 6.72 (d, 1H), 6.63(dd, 1H), 6.19 (m, 2H), 5.21 (s, 2H), 3.79 (m, 1H), 3.40 (s, 3H), 3.09(m, 6H), 2.73 (m, 4H), 2.56 (s, 2H), 2.19 (m, 6H), 2.07 (m, 6H), 1.96(s, 2H), 1.74 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1594-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-hydroxy-2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

Into a 10 m microwave tube was added EXAMPLE 158E (54 mg) and hydrogenchloride (1.25 M in methanol) (0.5 mL) in tetrahydrofuran (4 mL) to givea solution. The mixture was stirred at 60° C. in a CEM Discovermicrowave reactor for 20 minutes. the solvent was dried under vacuum andthe crude product was purified by preparative HPLC using a 250×50 mm C18column and eluting with 20-100% CH₃CN vs. 0.1% trifluoroacetic acid inwater. The trifluoroacetic acid salt was solved in dichloromethane withammonium and washed with saturated Na₂CO₃, dried over Na₂CO₄, filtered,and concentrated to afford the free base product. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 9.38 (s, 1H), 8.46 (d, 1H), 8.13 (d, 1H), 7.77(dd, 1H), 7.52 (d, 1H), 7.35 (d, 2H), 7.08 (m, 3H), 6.83 (t, 1H), 6.60(dd, 1H), 6.51 (d, 1H), 6.08 (m, 2H), 3.03 (m, 6H), 2.73 (m, 4H), 2.19(m, 6H), 2.00 (m, 9 H), 1.71 (m, 2H), 1,40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1602-(3-bromophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 160A methyl 2-(3-bromophenoxy)-4-fluorobenzoate

The title compound was prepared as described in EXAMPLE 3A by replacing2-methyl-5-indolol with 3-bromophenol.

EXAMPLE 160B methyl 2-(3-bromophenoxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 3G by replacingEXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE 160A,respectively.

EXAMPLE 160C methyl 2-(3-bromophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 380 by replacingEXAMPLE 38F with EXAMPLE 160B.

EXAMPLE 160D2-(3-bromophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 38H by replacingEXAMPLE 38G with EXAMPLE 160C.

EXAMPLE 160E2-(3-bromophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 160D and EXAMPLE 3I,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.29 (d, 1H),8.10 (m, 2H), 7.64 (d, 1H), 7.60 (dd, 1H), 7.40 (d, 2H), 7.15 (d, 2H),7.06 (t, 1H), 6.96 (m, 2H), 6.94 (d, 1H), 6.68 (m, 3H), 6.37 (d, 1H),5.84 (m, 2H), 4.15 (m, 2H), 3.65 (m, 1H), 3.09 (m, 6H), 2.99 (m, 5H),2.87 (s, 2H), 2.75 (m, 2H), 2.26 (m, 4H), 1.98 (m, 1H), 1.21 (s, 6H).

EXAMPLE 1614-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(3-iodophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 161A methy 4-fluoro-2-(3-iodophenoxy)benzoate

The title compound was prepared as described in EXAMPLE 3A by replacing2-methyl-5-indolol with 3-iodophenol.

EXAMPLE 161B methyl 2-(3-iodophenoxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 3G by replacingEXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE 161A,respectively.

EXAMPLE 161C methyl4-(4-((4-(4-chlorophenyl-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(3-iodophenoxy)benzoate

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLES 8F with EXAMPLE 161B.

EXAMPLE 161D4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(3-iodophenoxy)benzoicacid

The title compound was prepared as described in EXAMPLE 38H by replacingEXAMPLE 38G with EXAMPLE 161C.

EXAMPLE 161E4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(3-iodophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 161D and EXAMPLE 3I,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.34 (d, 1H),8.08 (d, 1H), 7.64 (m, 2H), 7.40 (d, 2H), 7.17 (m, 3H), 6.95 (m, 3H),6.71 (m, 2H), 6.37 (d, 1H), 4.15 (s, 2H), 3.83 (m, 1H), 3.15 (m, 8H),2.87 (s, 3H), 2.60 (m, 4H), 2.17 (m, 8H), 1.76 (m, 1H), 1.20 (s, 6H).

EXAMPLE 1622-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 162A tert-butyl4-(2-nitro-4-sulfamoylphenylamino)piperidine-1-carboxylate

The title compound was prepared by substituting tert-butyl4-aminopiperidine-1-carboxylate for 3-(N-morpholinyl)-1-propylamine inEXAMPLE 4A.

EXAMPLE 162B

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 162A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 162C2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(piperidin-4-ylamino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 162B for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 162DN-(4-(1-(2-(tert-butyldimethylsilyloxy)ethyl)piperidin-4-ylamino)-3-nitrophenylsulfonyl)-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 162C fortert-butyl pieperazien-1-carboxylate and2-(tert-butyldimethylsilyloxy)acetaldehyde for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

EXAMPLE 162E2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

A mixture of EXAMPLE 162D (270 mg) in anhydrous tetrahydrofuran (5 mL)and tetrabutyl ammonium fluoride (5 mL 1M in tetrahydrofuran) wasstirred at room temperature for 2 hours. the solvent was removed undervacuum. The residue was purified by reverse phase HPLC on a C18 columnusing a gradient of 40-70% acetonitrile/0.1% trifluoroacetic acid inwater to give the title compound as the trifluoroacetate salt. Thetrifluoroacetate salt was dissovled in dichloromethane (6 mL) and washedwith 50% aqueous NaHCO₃. The organic layer was dried over anhydrousNa₂SO₄ and concentrated to give the title compound. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.35 (d, 1H), 8.09 (d, 1H), 7.69 (dd, 1H), 7.61(d, 1H), 7.36 (d, 2H), 7.14 (m, 1H), 7.05 (m,3H), 6.88 (dd, 1H), 6.73(dd, 1H), 6.65 (dd, 1H), 6.60 (m, 1H), 6.40 (d, 1H), 3.85 (m, 1H), 3.68(m, 2H), 3.28 (m, 4H), 3.12 (m, 4H), 2.99 (m, 4H), 2.77 (s, 2H), 2.16(m, 8H), 1.98 (s, 2H), 1.83 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1632-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2-phenylethyl)-piperidin-4-yl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 162C fortert-butyl pieperazien-1-carboxylate and 2-phenylacetaldehyde for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.37 (d, 1H), 8.16 (d, 1H), 7.70 (dd, 1H), 7.59(d, 1H), 7.30 (m, 8H), 7.16 (m, 1H), 7.07 (m, 3H), 6.89 (d, 1H), 6.74(dd, 1H), 6.66 (dd, 1H), 6.62 (d, 1H), 6.42 (d, 1H), 3.84 (m, 1H), 3.27(m, 6H), 2.98 (m, 8H), 2.78 (s, 2H), 2.17 (m, 8H), 1.98 (s, 2H), 1.78(m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1644-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3,4-dichlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 164A Ethyl 2-(3,4-dichlorophenoxy)-4-fluorobenzoate

The title compound was prepared by substituting 2,3-dichlorophenol for2-methyl-5-indolol is EXAMPLE 3A.

EXAMPLE 164B Ethyl2-(3,4-dichlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 164A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 164C2-(3,4-dichlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 164B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 164D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3,4-dichlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 164C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H, ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.35 (d, 1H), 8.06 (s, 1H), 7.62 (d, 2H),7.31-7.40 (m, 3H), 7.04-7.10 (m, 2H), 6.98 (d, 1H), 6.98 (d, 1H),6.70-6.81 (m, 2H), 6.64 (dd, 1H), 6.42 (d, 1H), 3.79 (s, 1H), 3.19-3.27(m, 2H), 3.12 (s, 5H), 2.69-2.81 (m, 4H), 2.63 (s, 2H), 2.15-2.28 (m,8H), 2.08 (s, 2H), 1.98 (s, 3H), 1.77 (s, 1H), 1.36-1.45 (m, 2H), 1.24(s, 1H), 0.95 (s, 6H).

EXAMPLE 1652-(2-chloro-3,5-difluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 165A Ethyl 2-(2-chloro-3,5-difluorophenoxy)-4-fluorobenzoate

The title compound was prepared by substituting2-chloro-3,5-difluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 165B Ethyl2-(2-chloro-3,5-difluorophenoxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared by substituting piperazine for EXAMPLE3F and EXAMPLE 165A for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 165C Ethyl2-(2-chloro-3,5-difluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 60D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 165B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 165D2-(2-chloro-3,5-difluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 165C for EXAMPLE1E in EXAMPLE 1E.

EXAMPLE 165E2-(2-chloro-3,5-difluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 165D for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.30 (m, 1H), 8.06 (m, 1H), 7.68 (m, 2H), 7.36(d, 2H), 7.07 (d, 2H), 7.00 (d, 1H), 6.78 (m, 2H), 6.45 (d, 1H), 5.93(d, 1H), 3.77 (m, 1H), 3.12 (m, 4H), 2.76 (s, 3H), 2.21 (m, 6H), 2.07(m, 2H), 1.98 (s, 2H), 1.72 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1664-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 166A ethyl 4-fluoro-2-(3-methoxyphenoxy)benzoate

The title compound was prepared by substituting 3-methoxyphenol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 166B ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-methoxyphenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 166A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 166C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-methoxyphenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 166B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 166D

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 166C for EXAMPLE122C and EXAMPLE 3I for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.39 (d, 1H), 8.10 (br d, 1H), 7.73 (dd, 1H),7.57 (d, 1H), 7.37 (d, 2H), 7.05 (m, 4H), 6.68 (dd, 1H), 6.45 (dd, 1H),6.30 (m, 3H), 3.80 (br m, 1H), 3.64 (s, 3H), 3.18 (br m, 1H), 3.07 (brm, 4H), 2.80 (br m, 1H), 2.78 (s, 2H), 2.60 (s, 2H), 2.50 (s, 3H), 2.20(br m, 6H), 2.09 (br m, 2H), 1.98 (s, 2H), 1.78 (br m, 2H), 1.40 (br t,2H), 0.93 (s, 6H).

EXAMPLE 1674-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[3-hydroxymethyl)phenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 167A methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-formylphenoxy)benzoate

The title compound was prepared by substituting 3-hydroxybenzaldehydefor EXAMPLE 1D and EXAMPLE 214A for EXAMPLE 1C in EXAMPLE 1E.

EXAMPLE 167B4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-formylphenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 167A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 167C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-formylphenoxy)-N-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 167B for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 167D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[3-hydroxymethyl)phenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

EXAMPLE 167C (107 mg) was dissolved in ethanol (3 mL) andtetrahydrofuran (9 mL), and NaBH₄ (13 mg) was added and the mixturestirred at room temperature for 10 minutes. After carefully adding 2Naqueous HCl; (0.67 mL), the reaction was concentrated andd the crudematerial was purified by preparative HPLC using a C18 column, 250×50 mm,10μ, and eluting with a gradient of 20-100% CH₃CN vs. 0.1%trifluoroacetic acid in water, giving the product as a trifluoroacetatesalt. The salt was dissolved in dichloromethane (6 Na₂SO₄, filtered, andconcentrated to give the title compound. ¹H NMR (500 MHz,CDCl₃/methanol-d₄) δ 8.80 (d, 1H), 8.45 (br d, 1H), 8.03 (dd, 1H), 7.86(d, 1H), 7.39 (m, 1H), 7.27 (m, 3H), 7.09 (s, 1H), 6.95 (d, 4H), 6.60(dd, 1H), 6.12 (d, 1H), 4.67 (s, 2H), 3.63 (br s, 1H), 3.15 (br t, 4H),2.82 (br s, 1H), 2.80 (s, 3H), 2.35 (m, 5H), 2.28 (br t, 4H), 2.20 (brt, 2H), 2.10 (br m, 2H), 1.99 (s, 2H), 1.73 (m, 2H), 1.43 (t, 2H), 0.94(s, 6H).

EXAMPLE 1682-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 168A tert-butyl4-(benzyloxycarbonylamino)-4-methylpiperidine-1-carboxylate

1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (5.0 g),diphenylphosphoryl azide (DPPA, 4.58 mL), triethylamine (2.86 mL), andbenzyl alcohol (4.26 mL) were stirred in toluene (45 mL) at 110° C. for24 hours. The mixture was cooled, concentrated, and chromatographed onsilica gel using 10% ethyl acetate/hexanes as eluent to give the pureproduct.

EXAMPLE 168B tert-butyl 4-amino-4-methylpiperidine-1-carboxylate

EXAMPLE 168A (4.5 g) and ethanol (100 mL) were added to 20% Pd(OH)₂—C,wet (0.900 g) in a 250 mL SS pressure bottle and stirred for 3 hours at30 psi and room temperature. The mixture was filtered through a nylonmembrane and concentrated to give the product.

EXAMPLE 168C tert-butyl4-methyl-4-(2-nitro-4-sulfamoylphenylamino)piperidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 168B for3-(n-morpholinyl)-1-propylamine in EXAMPLE 4A.

EXAMPLE 168D 4-(4-methylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 168C for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 168E4-(1,4-dimethylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide

EXAMPLE 168D (1.33 g), iodomethane (0.29 mL), and triethylamine (0.65mL) in acetonitrile (20 mL) were stirred for 1 hour. The mixture wasconcentrated and chromatographed on silica gel using 10%methanol/dichloromethane as eluent to give the product.

EXAMPLE 168F2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE1E and EXAMPLE 168E for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.55 (m, 1H), 8.43 (d, 1H), 7.82 (d, 1H), 7.52(d, 1H), 7.43 (d, 1H), 7.38 (d, 2H), 7.18 (dd, 1H), 7.09 (d, 2H), 7.05(m, 1H), 6.76 (d, 2H), 6.34 (d, 1H), 2.94-3.12 (m, 11H), 2.70 (m, 4H),2.27 (m, 4H), 2.00 (s, 3H), 1.55 (s, 3H), 1.41 (m, 2H), 0.95 (s, 6H).

EXAMPLE 1692-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 168E for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.49 (m, 1H), 8.40 (d, 1H), 7.75 (d, 1H), 7.54(d, 1H), 7.37 (d, 2H), 7.27 (m, 1H), 7.22 (t, 1H), 7.07 (d, 2H), 7.00(d, 1H), 6.77 (d, 1H), 6.72 (d, 1H), 6.45 (d, 1H), 3.20 (m, 4H), 3.05(m, 6H), 2.88 (m, 2H), 2.73 (m, 4H), 2.27 (m, 4H), 2.20 (m, 2H), 1.99(s, 3H), 1.55 (s, 3H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 1702-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(2-methoxyethoxy)ethyl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}benzamide

A mixture of EXAMPLE 162C (100 mg), 1-bromo-2-(2-methoxyethoxy)ethane(52 mg), cesium carbonate (70 mg) in N,N-dimethylformamide was heated at60° C. overnight. The solvent was removed under vacuum. The residue waspurified by reverse phase HPLC on a C18 column using a gradient of40-70% acetonitrile/0.1% TFA in water to give the title compound as thetrifluoroacetate salt. The TFA salt was dissolved in dichloromethane (6mL) and washed with 50% aqueous NaHCO₃. The organic layer was dried overanhydrous Na₂SO₄ and concentrated to give the title compound. ¹H NMR(400 MHz, dimethylsulfoxide-d₆) δ 8.36 (d, 1H), 8.12 (d, 1H), 7.69 (dd,1H), 7.59 (d, 1H), 7.35 (d, 2H), 7.14 (m, 1H), 7.05 (m, 3H), 6.89 (m,1H), 6.74 (dd, 1H), 6.66 (dd, 1H), 6.60 (m, 1H), 6.40 (d, 1H), 3.81 (s,1H), 3.65 (t, 2H), 3.56 (m, 2H), 3.47 (m, 2H), 3.31 (m, 2H), 3.26 (m,3H), 3.18 (m, 2H), 3.13 (m, 2H), 2.97 (m, 2H), 2.77 (m, 4H), 2.21 (m,7H), 2.07 (m, 2H), 1.98 (s, 2H), 1.76 (m, 2H), 1.41 (t, 2H), 0.94 (s,6H).

EXAMPLE 1712-(2-chloro-3-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 171A 2-chloro-3-(methoxymethoxy)phenol

The title compound was prepared by substituting 2-chlorobenzene-1,3-diolfor EXAMPLE 158B in EXAMPLE 158C.

EXAMPLE 171B Methyl2-(2-chloro-3-(methoxymethoxy)phenoxy)-4-fluorobenzoate

The title compound was prepared by substituting 171A for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 171C Methyl2-(2-chloro-3-(methoxymethoxy)phenoxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared by substituting piperazine for EXAMPLE3F and EXAMPLE 171B for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 171D Methyl2-(2-chloro-3-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 60D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 171C for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 171E2-(2-chloro-3-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclchex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting 171D for EXAMPLE 1E inEXAMPLE 1F.

EXAMPLE 171F2-(2-chloro-3-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 171E for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 171G2-(2-chloro-3-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 171F for EXAMPLE158 in EXAMPLE 159. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 10.13 (s,1H), 8.41 (d, 1H), 8.08 (d, 1H), 7.77 (dd, 1H), 7.60 (d, 1H), 7.35 (d,2H), 7.07 (m, 3H), 6.89 (t, 1H), 6.67 (dd, 1H), 6.59 (m, 1H), 6.19 (d,1H), 6.08 (d, 1H), 3.80 (m, 1H), 3.09 (m, 6H), 2.79 (m, 4H), 2.57 (s,3H), 2.21 (m, 6H), 2.08 (m, 2H), 1.97 (s, 2H), 1,74 (m, 2H), 1.40 (t,2H), 0.94 (s, 6H).

EXAMPLE 1722-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(3-phenylpropyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 162C fortert-butyl pieperazien-1-carboxylateand 3-phenylpropanal for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.36 (d, 1H), 8.10 (m, 1H), 7.69 (m, 1H), 7.59(d, 1H), 7.36 (d, 2H), 7.31 (m, 2H), 7.22 (m, 3H), 7.14 (m, 1H), 7.07(d, 2H), 7.02 (d, 1H), 6.88 (d, 1H), 6.74 (dd, 1H), 6.65 (dd, 1H), 6.60(m, 1H), 6.41 (d, 1H), 3.84 (m, 1H), 3.29 (m, 4H), 3.12 (m, 4H), 2.81(m, 5H), 2.64 (m, 2H), 2.22 (m, 6H), 2.10 (m, 2H), 1.99 (m, 2H), 1.90(m, 2H), 1.75 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 1732-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting 1-bromo-2-methoxyethanefor 1-bromo-2-(2-methoxyethoxy)ethane in EXAMPLE 170. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.36 (d, 1H), 8.13 (d, 1H), 7.69 (dd, 1H), 7.59(d, 1H), 7.36 (d, 2H), 7.15 (m, 1H), 7.06 (m, 3H), 6.89 (dd, 1H), 6.74(dd, 1H), 6.66 (dd, 1H), 6.61 (d, 1H), 6.41 (d, 1H), 3.82 (m, 1H), 3.57(t, 2H), 3.38 (m, 4H), 3.13 (m, 6H), 2.99 (m, 2H), 2.89 (m, 1H), 2.78(s, 3H), 2.21 (m, 6H), 2.08 (m, 2H), 1.98 (s, 2H), 1.78 (m, 2H), 1.41(t, 2H), 0.94 (s, 6H).

EXAMPLE 1742-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-ethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 47A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.34 (d, 1H), 8.07 (s, 1H), 7.58-7.71 (m, 2H),7.36 (d, 2H), 7.00-7.14 (m, 4H), 6.85-6.94 (m, 1H), 6.73 (dd, 1H), 6.64(dd, 1H), 6.59 (d, 1H), 6.39 (d, 1H), 3.86 (s, 1H), 3.11 (s, 5H), 2.94(d, 2H), 2.72-2.81 (m, 3H), 2.12-2.27 (m, 8H), 1.98 (s, 2H), 1.77 (s,2H), 1.41 (t, 2H), 1.18 (t, 3H), 0.94 (s, 6H).

EXAMPLE 1752-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 41A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.98 (bs, 1H), 8.34 (d, 1H), 8.04 (s, 1H),7.59-7.73 (m, 2H), 7.36 (d, 2H), 7.14 (t, 1H), 7.04-7.09 (m, 2H), 7.01(d, 1H), 6.87 (d, 1H), 6.72 (dd, 1H), 6.61-6.66 (m, 1H), 6.58 (s, 1H),6.39 (d, 1H), 3.90 (s, 1H), 3.11 (s, 6H), 2.73-2.83 (m, 2H), 2.14-2.28(m, 9 H), 1.98 (s, 3H), 1.76 (s, 2H), 1.41 (t, 3H), 1.14-1.29 (m, 6H),0.94 (s, 6H).

EXAMPLE 1764-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-hydroxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 176A Ethyl 2-(3-hydroxyphenoxy)-4-fluorobenzoate

The title compound was prepared by substitutingresommolfor2-methyl-5-indololIn EXAMPLE 3A.

EXAMPLE 176B Ethyl2-(3-hydroxyphenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 176A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 176C Ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-(methoxymethoxy)phenoxy)benzoate

A suspension of EXAMPLE 176B (0.295 g), methoxymethyl chloride (0.117mL) and cesium carbonate (0.334 g) in N, N-dimethylformamide (3 mL) wasstirred at 60° C. for 16 hours. The reaction mixture was partitionedbetween dichloromethane and water. The water layer was extracted withdichloromethane. The combined organic extracts were washed with water(2×), dried over magnesium sulfate, filtered and concentrated. The crudeproduct was purified by flash chromotography (silica gel, 5%-20% ethylacetate/hexanes) providing the product.

EXAMPLE 176D4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-(methoxymethoxy)phenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 176C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 176E4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-(meth)phenoxy)-N-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 176D for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 176F4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-hydroxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

A suspension of EXAMPLE 176E (35.5 mg) in tetrahydrofuran (3 mL) and HCl(1.25 M in methanol, 2 mL) was stirred for 1 hour at 60° C. The productwas concentrated. The crude product was purified by RP HPLC (C8,30%-100% CH₃CN/water/0.1% TFA) to yield the product. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 9.31 (s, 1H), 8.10 (s, 1H), 7.66-7.73 (m, 2H),7.56 (d, 1H), 7.34-7.38 (m, 2H), 7.02-7.09 (m, 2H), 6.95-7.02 (m, 1H),6.65 (dd, 1H), 6.34 (s, 1H), 6.29 (d, 1H), 6.20 (d, 1H), 6.14 (d, 1H),4.14 (dd, 1H), 3.75 (s, 1H), 3.05 (d, 4H), 2.68-2.80 (m, 3H), 2.20 (d,6H), 2.08 (d, 2H), 1.97 (s, 2H), 1.69-1.79 (m, 2H), 1.63 (s, 1H), 1.39(d, 2H), 1.21-1.36 (m, 9 H), 0.94 (s, 6H).

EXAMPLE 1772-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 177A 2-chloro-3-fluorophenol

To a solution of 2-chloro-3-fluorophenylboronic acid (5.0 g) intetrahydrofuran (50 mL) and 1 M aqueous NaOH (30 mL) at 0° C. 30%hydrogen peroxide solution (4 mL), and the reaction was stirred for 2hours. The reaction was quenched with saturated aqueous Na₂S₂O₃solution, acidified with concentrated aqueous HCl, and extracted twicewith ethyl acetate. The combined extracts were washed with brine,concentrated, and chromatographed on silica gel using 10% ethylacetate/hexanes as eluent to give the product.

EXAMPLE 177B methyl 2-(2-chloro-3-fluorophenoxy)-4-fluorobenzoate

The title compound was prepared by substituting EXAMPLE 177A for2-methyl-5-indolol and methyl 2,4-difluorobenzoate for ethyl2,4-difluorobenzoate EXAMPLE 3A.

EXAMPLE 177C methyl2-(2-chloro-3-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 177B for methyl2-bromo-4-fluorobenzoate and EXAMPLE 3F for EXAMPLE 1B in EXAMPLE 1C.

EXAMPLE 177D2-(2-chloro-3-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 177C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 177E2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 177D for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.39 (d, 1H), 8.15 (m, 1H), 7.76 (d, 1H), 7.58(d, 1H), 7.37 (d, 2H), 7.15 (d, 1H), 7.07 (d, 2H), 7.02 (m, 1H), 6.88(t, 1H), 6.77 (d, 1H), 6.44 (s, 1H), 6.33 (d, 1H), 3.91 (m, 1H), 3.18(m, 4H), 3.07 (m, 2H), 2.77 (m, 6H), 2.27 (m, 4H), 2.19 (m, 4H), 1.99(s, 3H), 1.77 (m, 2H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 1782-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 177D for EXAMPLE1E and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.28 (d, 1H), 8.10 (m, 1H), 7.65 (d, 1H), 7.62(d, 1H), 7.37 (d, 2H), 7.08 (d, 2H), 6.98 (m, 2H), 6.80 (t, 1H), 6.74(d, 1H), 6.37 (d, 1H), 6.22 (d, 1H), 3.89 (m, 1H), 3.28 (m, 4H), 3.09(m, 6H), 2.84 (m, 4H), 2.73 (m, 3H), 2.40 (m, 2H), 2.23 (m, 6H), 2.01(m, 1H), 1.99 (s, 3H), 1.68 (m, 2H), 1.55 (m, 4H), 1.41 (t, 2H), 0.94(s, 6H).

EXAMPLE 1792-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE122C in EXAMPLE 137. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.50 (brt, 1H), 8.38 (d, 1H), 7.75 (dd, 1H), 7.63 (d, 1H), 7.37 (m, 3H), 7.06(m, 3H), 6.98 (d, 1H), 6.92 (ddd, 1H), 6.70 (dd, 1H), 6.56 (dd, 1H),6.24 (d, 1H), 3.47 (dd, 2H), 3.05 (br m, 4H), 2.90 (br m, 2H), 2.75 (s,2H), 2.60 (s, 6H), 2.20 (br m, 6H), 1.98 (s, 2H), 1.90 (m, 2H) 1.40 (t,2H), 0.93 (s, 6H).

EXAMPLE 1804-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 180A ethyl 4-fluoro-2-(2-methoxyphenoxy)benzoate

The title compound was prepared by substituting 2-methoxyphenol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 180B ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(2--methoxyphenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 180A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 180C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(2-methoxyphenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 180B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 180D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 180C for EXAMPLE122C and EXAMPLE 3I for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.47 (d, 1H), 8.15 (br d, 1H), 7.83 (dd, 1H),7.57 (d, 1H), 7.37 (d, 2H), 7.13 (d, 1H), 7.05 (m, 4H), 6.80 (m, 2H),6.60 (dd, 1H), 6.07 (d, 1H), 3.80 (br m, 1H), 3.73 (s, 3H), 3.22 (br m,1H), 3.05 (br m, 1H), 3.00 (br m, 4H), 2.75 (s, 2H), 2.62 (br s, 2H),2.50 (s, 3H), 2.20 (br m, 6H), 2.04 (br m, 2H), 1.98 (s, 2H), 1.73 (brm, 2H), 1.40 (br t, 2H), 0.93 H).

EXAMPLE 1814-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 181A ethyl 4-fluoro-2-(2-methylphenoxy)benzoate

The title compound was prepared by substituting 2-methylphenol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 181B ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(2-methylphenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 181A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 181C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(2-methylphenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 181B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 181D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 181C for EXAMPLE122C and EXAMPLE 3I for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.40 (d, 1H), 8.12 (br d, 1H), 7.73 (dd, 1H),7.54 (d, 1H), 7.37 (d, 2H), 7.10 (m, 2H), 7.05 (d, 2H), 6.96 (m, 1H),6.84 (m, 1H), 6.64 (dd, 1H), 6.46 (d, 1H), 6.20 (d, 1H), 3.80 (br m,1H), 3.10 (br m, 3H), 3.05 (br m, 4H), 2.77 (s, 2H), 2.76 (br m, 2H),2.58 (s, 2H), 2.20 (br m, 6H), 2.16 (s, 3H), 2.09 (br m, 2H), 1.98 (s,2H), 1.78 (br m, 2H), 1.40 (br t, 2H), 0.93 (s, 6H).

EXAMPLE 1824-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 182A ethyl 4-fluoro-2-(3-methylphenoxy)benzoate

The title compound was prepared by substituting 3-methylphenol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 182B

ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-methylphenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 182A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 182C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-methylphenoxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 182B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 182D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 182C for EXAMPLE122C and EXAMPLE 3I for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.40 (d, 1H), 8.10 (br d 3 1H), 7.74 (dd, 1H),7.56 (d, 1H), 7.36 (d, 2H), 7.05 (m, 4H), 6.73 (d, 1H), 6.67 (dd, 1H),6.52 (m, 2H), 6.29 (d, 1H), 3.80 (br m, 1H), 3.10 (br m, 3H), 3.05 (brm, 4H), 2.77 (s, 2H), 2.76 (br m, 2H), 2.58 (s, 2H), 2.20 (br m, 6H),2.16 (s, 3H), 2.09 (br m, 2H), 1.98 (s, 2H), 1.78 (br m, 2H), 1.40 (brt, 2H), 0.93 (s, 6H).

EXAMPLE 1832-(2-chlorophenoxy)-4-(4-{[6-(4-chlorophenyl)-1,3-benzodioxol-5-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 183A 6-(4-chlorophenyl)benzo[d][1,3]dioxole-5-carbaldehyde

To a solution of 6-bromobenzo[d][1,3]dioxole-5-carbaldehyde (4.6 g),4-chlorophenylboronic acid (3.78 g) andtetrakis(triphenylphosphine)palladium(0) (0.232 g) in toluene (80 mL)and methanol (30 mL) was added 2 N aqueous Na₂CO₃ (30 mL). The mixturewas stirred at reflux overnight. The mixture was diluted with ether (400mL) and washed with water, brine and dried over Na₂O₄. After filtratinand concentration of the solvent, the residue was loaded on a column andeluted with 3% ethyl acetate in hexane to give the product.

EXAMPLE 183B methyl2-(2-chlorophenoxy)-4-(4-((6-(4-chlorophenyl)benzo[d][1,3]dioxol-5-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLE 38E with EXAMPLE 183A.

EXAMPLE 183C

2-(2-chlorophenoxy)-4-(4-((6-(4-chlorophenyl)benz[d][1,3]dioxol-5-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 38H by replacingEXAMPLE 38G with EXAMPLE 183B.

EXAMPLE 183D2-(2-chlorophenoxy)-4-(4-{[6-(4-chlorophenyl)-1,3-benzodioxol-5-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 183C and EXAMPLE 3I,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.35 (d, 1H),8.07 (d, 1H), 7.73 (dd, 1H), 7.64 (d, 1H), 7.38 (m, 6H), 7.02 (m, 3H),6.86 (m, 1H), 6.79 (s, 1H), 6.72 (dd, 1H), 6.51 (d, 1H), 6.28 (d, 1H),6.04 (s, 2H), 3.81 (m, 1H), 3.25 (s, 3H), 3.08 (m, 6H), 2.72 (m, 5H),2.33 (m, 4H), 2.07 (m, 2H), 1.74 (m, 1H).

EXAMPLE 1842-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 184A 4-(4-methylpiperazin-1-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting4-methylpiperazin-1-amine for 3-(N-morpholinyl)-1-propylamine in EXAMPLE4A.

EXAMPLE 184B2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 9.14 (s, 1H), 8.38 (d, 1H), 7.77 (dd, 1H), 7.55(m, 2H), 7.37 (m, 3H), 7.08 (m, 3H), 6.95 (m, 1H), 6.72 (dd, 1H), 6.62(d, 1H), 6.27 (d, 1H), 3.10 (m, 4H), 2.97 (m, 4H), 2.77 (s, 2H), 2.45(s, 3H), 2.20 (m, 6H), 1.97 (s, 2H), 1.40 (t, 2H), 0.94 (m, 6H).

EXAMPLE 1852-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 38H for EXAMPLE1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 9.15 (s, 1H), 8.34 (d, 1H), 7.68 (dd, 1H), 7.57(d, 1H), 7.51 (d, 1H), 7.39 (d, 2H), 7.16 (m, 3H), 6.92 (m, 1H), 6.75(dd, 1H), 6.68 (dd, 1H), 6.64 (m, 1H), 6.43 (d, 1H), 4.15 (s, 2H), 3.15(m, 6H), 2.99 (m, 6H), 2.88 (s, 2H), 2.49 (s, 3H), 2.26 (m, 4H), 2.17(s, 2H), 1.20 (s, 6H).

EXAMPLE 1864-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 145B for EXAMPLE1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 9.15 (s, 1H), 8.34 (d, 1H), 7.74 (dd, 1H), 7.60(d, 1H), 7.54 (d, 1H), 7.40 (d, 2H), 7.16 (d, 2H), 6.87 (m, 2H), 6.74(dd, 1H), 6.46 (d, 1H), 6.34 (m, 1H), 4.15 (s, 2H), 3.14 (m, 6H), 3.00(m, 4H), 2.88 (s, 2H), 2.52 (s, 3H), 2.26 (m, 4H), 2.17 (s, 2H), 1.21(s, 6H).

EXAMPLE 1872-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 187A2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)piperidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 162A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 187B2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(piperidin-4-ylamino)phenylsulfonyl)benzamide

EXAMPLE 187A was treated with TFA (0.5 mL) and stirred for 6 hours. Theproduct was concentrated and purified by RP HPLC (C8, 30%-100%CH₃CN/water/0.1% TFA).

EXAMPLE 187C2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

A suspension of EXAMPLE 187B (50 mg), cyclopropanecarbaldehyde (100 mg)and MP-CNBH₃ resin (0.2 g, 2.43 mmol/g) in dichloromethane (4mL)/methanol (3 mL) was shaken for 16 hours at room temperature. Theproduct was filtered, washed with dichloromethane/methanol andconcentrated. The crude product was purified by RP HPLC (C8, 30%-100%CH₃CN/water/0.1% TFA) to yield the product. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.35 (s, 1H), 8.10 (s, 1H), 7.67-7.75 (m, 1H),7.60 (d, 1H), 7.36 (d, 2H), 7.15 (t, 1H), 7.07 (d, 3H), 6.89 (d, 1H),6.73 (dd, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 6.40 (s, 1H), 3.86 (s, 1H),3.12 (s, 5H), 2.71-2.80 (m, 3H), 2.13-2.28 (m, 9H), 1.98 (s, 3H), 1.79(s, 1H), 1.41 (t, 2H), 0.99-1.11 (m, 2H), 0.94 (s, 6H), 0.84 (d, 1H),0.63 (d, 2H), 0.33 (s, 2H).

EXAMPLE 1882-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 188A tert-butyl4-(4-(N-(2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)piperadine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE1F and EXAMPLE 162A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 188B2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(piperidin-4-ylamino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 188A for EXAMPLE187A is EXAMPLE 187B.

EXAMPLE 188C2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 188B for EXAMPLE187B in EXAMPLE 187C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.41 (d,1H), 8.13 (s, 1H), 7.79 (dd, 1H), 7.58 (d, 1H), 7.33-7.40 (m, 3H),7.04-7.16 (m, 4H), 6.94 (t, 1H), 6.72 (dd, 1H), 6.61 (s, 1H), 6.27 (d,1H), 3.91 (s, 1H), 3.44 (s, 2H), 3.02-3.15 (m, 5H), 2.95 (s, 2H),2.69-2.82 (m, 3H), 2.13-2.28 (m, 8H), 1.97 (s, 3H), 1.83 (s, 2H),1.32-1.46 (m, 3 H), 0.99-1.10 (m, 1H), 0.94 (s, 6H), 0.76-0.90 (m, 1H),0.59-0.71 (m, 2H), 0.34 (d, 2H).

EXAMPLE 1892-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(dimethylamino)-2-oxoethyl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}benzamide

The title compound was prepared by substituting2-chloro-N,N-dimethylacetamide for 1-bromo-2-(2-methoxyethoxy)ethane inEXAMPLE 170. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 9.63 (s, 1H), 8.46(s, 1H), 8.21 (m, 1H), 7.78 (m, 1H), 7.53 (d, 1H), 7.40 (d, 2H), 7.22(m, 2H), 7.11 (d, 2H), 6.96 (d, 1H), 6.82 (dd, 1H), 6.72 (m, 2H), 6.57(s, 1H), 4.28 (m, 2H), 3.85 (m, 8H), 3.16 (m, 4H), 2.96 (m, 7H), 2.82(m, 2H), 2.11 (m, 8H), 1.47 (s, 2H), 0.96 (s, 6H).

EXAMPLE 1902-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-morpholin-4-ylethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 162C fortert-butyl pieperazien-1-carboxylate and 2-morpholinoacetaldehyde for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.46 (d, 1H), 8.29 (d, 1H), 7.78 (dd, 1H), 7.53(d, 1H), 7.41 (d, 2H), 7.21 (m, 2H), 7.11 (d, 2H), 6.96 (dd, 1H), 6.83(dd, 1H), 6.73 (dd, 1.83 Hz, 1H), 6.69 (m, 1H), 6.58 (s, 1H), 3.82 (m,10H), 3.27 (m, 4H), 3.09 (m, 6H), 2.81 (m, 7H), 2.23 (m, 2H), 2.15 (m,2H), 2.04 (s, 2H), 1.93 (m, 2H), 1.48 (t, 2H), 0.96 (s, 6H).

EXAMPLE 191N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamideEXAMPLE 191A 4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting4-(aminomethyl)tetrahydro-2H-pyran-4-amine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.

EXAMPLE 191BN-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE1F and EXAMPLE 191A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.57 (t, 1H), 8.47 (d, 1H), 8.18(s, 3H), 7.79(dd, 1H), 7.53 (d, 1H), 7.41 (d, 2H), 7.34 (d, 1H), 7.24 (t, 1H), 7.11(d, 2H), 7.01-7.03 (m, 2H), 6.82 (dd, 1H), 6.73-6.76 (m, 2H), 6.56 (s,1H), 3.85 (d, 2H), 3.71-3.73 (m, 4H), 3.14 (br s, 2H), 2.23 (s, 2H),2.04 (m, 2H), 1.82-1.87 (m, 2H), 1.70-1.75 (m, 2H), 1.47 (t, 2H), 0.96(s, 6H).

EXAMPLE 1922-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 192A

The title compound was prepared by substituting4-(aminomethyl)-1-methylpiperidin-4-ol for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.

EXAMPLE 192B2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE1F and EXAMPLE 192A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 9.38 (s, 1H), δ 8.65 (t, 1H), 8.46 (d, 1H), 7.74(dd, 1H), 7.53 (d, 1H), 7.40 (d, 2H), 7.19-7.22 (m, 2H), 7.11 (d, 2H),6.97 (dd, 1H), 6.82 (dd, 1H), 6.70-6.74 (m, 2H), 6.57 (s, 1H), 3.60 (d,2H), 3.47 (d, 2H), 3.10-3.17 (m, 4H), 2.80-2.81 (m, 4H), 2.23 (s, 2H),2.04 (s, 2H), 1.76-1.85 (m, 4H), 1.47 (t, 2H), 0.96 (s, 6H).

EXAMPLE 1934-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 154E and EXAMPLE 49C,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.15 (s, 1H),8.51 (d, 1H), 8.16 (d, 1H), 7.82 (dd, 1H), 7.54 (d, 1H), 7.31 (m, 4H),7.08 (m, 4H), 6.60 (dd, 1H), 6.36 (s, 1H), 6.08 (d, 1H), 3.92 (m, 2H),3.74 (m, 1H), 3.04 (m, 7H), 2.71 (m, 3H), 2.16 (m, 6H), 1.99 (m, 4H),1.49 (m, 10H), 0.92 (s, 6H).

EXAMPLE 1942-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 194A (S)-tert-butyl3-(2-nitro-4-sulfamoylphenylamino)pyrrolidine-1-carboxylate

The title compound was prepared by substituting (S)-tert-butyl3-aminopyrrolidine-1-carboxylate for tert-butyl4-aminopiperidine-1-carboxylate in EXAMPLE 140A.

EXAMPLE 194B (S)-tert-butyl3-(4-(N-(2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)pyrrolidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 194A for EXAMPLE1G and EXAMPLE 36C for EXAMPLE 1F in EXAMPLE 1H.

EXAMPLE 194C(S)-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(pyrrolidin-3-ylamino)phenylsuflonyl)benzamide

The title compound was prepared by substituting EXAMPLE 194B for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 194D2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

To a solution of EXAMPLE 194C (470 mg) in tetrahydrofuran (3 mL) andacetic acid (1 ml, ) was added 37% formaldehyde solution in water (0.42mL) and MP-CNBH₃ resin (947 mg, 2.38 mmol/g)). The reaction mixture wasstirred overnight at room temperature. The resin was filtered off andreaction mixture was then concentrated. The residue was purified byflash chromatography, eluting with ethyl acetate, followed by a gradientof 3-10% methanol/dichloromethane. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.42 (d, 1H), 8.34 (m, 1H), 7.78 (dd, 1H), 7.53(d, 1H), 7.36 (d, 2H), 7.19 (t, 1H), 7.08 (m, 3H), 6.95 (m, 1H), 6.76(dd, 1H), 6.67 (m, 2H), 6.45 (d, 1H), 3.53 (m, 2H), 3.16 (m, 7H), 2.83(m, 4H), 2.61 (br m, 1H), 2.27 (m, 4H), 2.18 (m, 3H), 1.98 (m, 3H), 1.41(m, 2H), 0.94 (s, 6H).

EXAMPLE 1952-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 195A (R)-tert-butyl3-(2-nitro-4-sulfamoylphenylamino)pyrrolidine-1-carboxylate

The title compound was prepared by substituting (R)-tert-butyl3-aminopyrrolidine-1-carboxylate for tert-butyl4-aminopiperidine-1-carboxylate in EXAMPLE 140A.

EXAMPLE 195B (R)-tert-butyl3-(4-(N-(2-(3-chloropbenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)pyrrolidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 195A for EXAMPLE1G and EXAMPLE 36C for EXAMPLE 1F in EXAMPLE 1H.

EXAMPLE 195C(R)-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(pyrrolidin-3-ylamino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 195B for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 195D2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 195C for EXAMPLE194C in EXAMPLE 194D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 8.36 (d,1H), 8.23 (m, 1H), 7.72 (dd, 1H), 7.59 (d, 1H), 7.36 (d, 2H), 7.16 (t,1H), 7.06 (m, 2H), 6.98 (m, 1H), 6.90 (dd, 1H), 6.73 (dd, 1H), 6.64 (m,2H), 6.41 (d, 1H), 4.01 (s, 1H), 3.28 (m, 2H), 3.24 (m, 1H), 3.13 (m,5H), 2.76 (m, 2H), 2.69 (m, 3H), 2.56 (m, 1H), 2.24 (m, 7H), 1.90 (br s,2H), 1.41 (m, 2H), 0.94 (s, 6H).

EXAMPLE 197(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[3-(1H-pyrrol-2-yl)phenoxy]benzamide

A mixture of EXAMPLE 161 (0.095 g),1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid (0.025 g),tetrakis(triphenylphosphine)palladium(0) (0.012 g), and CsF (0.046 g) indimethoxyethane (2 mL) and methanol (1 mL) was heated in a CEM Discovermicrowave reactor (80° C., 20 minutes). The reaction mixture waspartitioned between water and ethyl acetate. The organic layer wasseparated, and the aqueous layer was extracted with additional ethylacetate. The combined organic layers were washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was then treated with 4 NHCl in dioxane. The solvent was removed, and the residue was purified byreverse phase Prep HPLC to give the title compound. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.21 (s, 1H), 8.39 (s, 1H), 8.04 (d, 1H), 7.70(d, 1H), 7.57 (d, 1H), 7.34 (d, 2H), 7.11-7.25 (m, 5H), 7.04 (d, 2H),6.96 (d, 1H), 6.80 (s, 1H), 6.66 (d, 2H), 6.48 (d, 1H), 6.41 (s, 1H),6.28 (s, 1H), 6.08 (d, 1H), 3.05 (s, 6H), 2.73 (s, 2H), 2.18-2.24 (m,6H), 1.74 (s, 3H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 1984-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(3-fluorophenoxy)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 112C for EXAMPLE1F and EXAMPLE 192A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.44 (s, 1H), 8.31 (d, 1H), 7.92 (s, 1H),7.63-7.66 (m, 2H), 7.36 (d, 2H), 7.07 (d, 2H), 6.99 (d, 1H), 6.71 (dd,1H), 6.62-6.65 (m, 1H), 6.47 (dd, 1H), 6.36-6.40 (m, 2H), 5.16 (s, 1H),3.09 (s, 6H), 2.92 (br s, 2H), 2.76 (a, 2H), 2.62-2.64 (m, 2H),2.18-2.23 (m, 6H), 1.93 (d, J=5.49 Hz, 2H), 1.72-1.76 (m, 4H), 1.41 (t,2H), 0.94 (s, 6H).

EXAMPLE 1992-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 9.12 (s, 1H), 8.33 (d, 1H), 7.66 (dd, 1H), 7.57(d, 1H), 7.50 (d, 1H), 7.36 (d, 2H), 7.17 (t, 1H), 7.07 (d, 2H), 6.91(m, 1H), 6.75 (dd, 1H), 6.68 (dd, 1H), 6.63 (m, 1H), 6.42 (d, 1H), 3.14(m, 4H), 2.96 (m, 6H), 2.78 (s, 2H), 2.45 (s, 3H), 2.21 (m, 6H), 1.98(s, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 2004-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 200A 2,3-difluoro-4-nitrophenol

A solution of 2,3-difluoro-4-nitroanisole (10 g) in 48% HBr (60 mL) and30% HBr in acetic acid (30 mL) was stirred at 120° C. overnight. Themixture was cooled to room temperature and extracted with ethyl acetate(3×200 ml) and the combined extracts were washed with brine and driedover Na₂SO₄. Filtration and evaporation of the solvent gave the product.

EXAMPLE 200B 6,7-difluoro-1H-indol-5-ol

The title compound was prepared as in EXAMPLE 154A by replacing2-fluoro-4-nitrophenol with EXAMPLE 200A.

EXAMPLE 200C methyl 2-(6,7-difluoro-1H-indol-5-yloxy)-4-fluorobenzoate

The title compound was prepared as described in EXAMPLE 3A by replacing2-methyl-5-indolol with EXAMPLE 200B.

EXAMPLE 200D methyl2-(6,7-difluoro-1H-indo-5-yloxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 3G by replacingEXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE 200C respectively.

EXAMPLE 200E methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6,7-difluoro-1H-indol-5-yloxy)benzoate

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLE 38F and EXAMPLE 38E with EXAMPLE 200D and EXAMPLE 60D.

EXAMPLE 200F4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6,7-difluoro-1H-indol-5-yloxy)benzoicacid

The title compound was prepared as described in EXAMPLE 38H by replacingEXAMPLE 38G with EXAMPLE 200E.

EXAMPLE 200G4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 200F and EXAMPLE 3I,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.63 (s, 1H),8.40 (d, 1H), 8.06 (d, 1H), 7.72 (dd, 1H), 7.59 (d, 1H), 7.35 (m, 3H),7.05 (d, 2H), 6.96 (d, 1H), 6.72 (d, 1H), 6.64 (dd, 1H), 6.36 (d, 1H),6.24 (d, 1H), 3.74 (m, 1H), 3.12 (m, 8H), 2.73 (s, 3H), 2.55 (m, 2H),2.14 (m, 10H), 1.74 (m, 3H), 1.39 (t, 2H), 0.93 (s, 6H).

EXAMPLE 2014-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 200F and EXAMPLE 49C,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.64 (s, 1H),8.40 (d, 1H), 8.09 (s, 1H), 7.70 (dd, 1H), 7.58 (d, 1H), 7.35 (m, 4H),7.05 (d, 2H), 6.92 (d, 1H), 6.64 (m, 2H), 6.36 (d, 1H), 6.23 (s, 1H),3.92 (m, 2H), 3.67 (m, 1H), 3.01 (m, 8H), 2.73 (s, 2H), 2.25 (m, 8H),1.97 (m, 5H), 1.53 (m, 8H), 0.94 (m, 6H).

EXAMPLE 202 tert-butyl4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)amino]carbonyl}phenoxy)-1H-indole-1-carboxylateEXAMPLE 202A ethyl 2-(1H-indol-4-yloxy)-4-fluorobenzoate

The title compound was prepared by substituting 4-hydroxyindole for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 202B ethyl2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 202A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 202C2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 202B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 202D4-(4-{[2-(4-chlorophenyl)-4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 202C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H, except 2-10% methanol inCH₂Cl₂ was used for the chromatography.

EXAMPLE 202E tert-butyl4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)amino]carbonyl}phenyoxy)-1H-indole-1-carboxylatebis(2,2,2-trifluoroacetate)

EXAMPLE 202D (0.58 g) was dissolved in CH₂Cl₂ (30 mL), thendi-tert-butyl dicarbonate (0.14 g) and 4-dimethylaminopyridine (0.02 g)was added and the reaction stirred at room temperature for 60 hours. Thereaction was then filtered through celite,c oncentrated, and the crudewas purified by preparative HPLC using a 250×50 mm C18 column, elutingwith 20-100% CH₃CN vs. 0.1% trifluoroacetic acid in water, giving theproduct as a trifluoroacetate salt. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.80 (v br s, 1H), 9.65, 9.45 (both v br s,total 2H), 8.55 (d, 1H), 8.12 (br d, 1H), 7.80 (dd, 1H), 7.72 (d, 1H),7.61 (d, 1H), 7.55 (d, 1H), 7.40 (d, 2H), 7.19 (d, 1H), 7.10 (m, 3H),6.80 (dd, 1H), 6.59 (d, 1H), 6.43 (s, 1H), 6.41 (d, 1H), 4.05 (v br s,1H), 3.85 (v br s, 1H), 3.60, 3.50, 3.40 (all v br m, total 10H), 3.10(v br m, 2H), 2.95, 2.90 (both br m, total 5H), 2.20 br m, 4H), 2.05 (brs, 2H), 1.80 (br m, 1H), 1.67 (s, 9 H), 1.45 (br t, 2H), 0.95 (s, 6H).

EXAMPLE 2032-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 203A4-(4-(dimethylamino)cyclohexylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting N¹,N¹-dimethylcyclohexane-1,4-diamine for 1-isopropylpiperidin-4-amine inEXAMPLE 41A.

EXAMPLE 203B2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 203A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) δ 9.16 (d, 1H), 8.31-8.39 (m, 2H), 8.03-8.07 (m, 1H), 7.46(d, 2H), 7.08-7.17 (m, 4H), 7.00-7.04 (m, 1H), 6.91-6.99 (m, 2H), 6.82(dd, 1H), 6.69 (d, 1H), 3.44-3.52 (m, 1H), 3.14-3.20 (m, 4H), 2.84 (s,2H), 2.64 (s, 1H), 2.49 (s, 6H), 2.31 (t 2H), 2.22-2.28 (m, 4H),2.09-2.15 (m, 2H), 2.05 (s, 2H), 1.97-2.02 (m, 2H), 1.47-1.56 (m, 2H),1.42 (t, 2H), 1.27-1.37 (m, 2H), 1.25 (s, 1H), 0.93-0.98 (m, 6H).

EXAMPLE 2042-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 204A4-(4-(diethylamino)cyclohexylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substitutingN¹,N¹-diethylcyclohexane-1,4-diamine for 1-isopropylpiperidin-4-amine inEXAMPLE 41A.

EXAMPLE 204B2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 204A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-₅) δ9.18 (d, 1H), 8.32-8.39 (m, 2H), 8.05-8.09 (m, 1H), 7.46(d, 2H), 7.15 (t, 1H), 7.08-7.13 (m, 3H), 6.98-7.05(m, 2H), 6.94 (dd,1H), 6.82 (dd, 1H), 6.69 (d, 1H), 3.43-3.50 (m, 1H), 3.13-3.19 (m, 4H),2.84 (s, 2H), 2.72 (t, 1H), 2.63 (q, 4H), 2.31 (t, 2H), 2.22-2.28 (m,4H), 2.11 (d, 2H), 2.00 (s, 2H), 1.91 (d, 2H), 1.40-1.48 (m, 4H),1.24-1.34 (m, 2H), 1.10 (t, 6H), 0.93-0.99 (m, 6H).

EXAMPLE 205Trans-2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 205Atrans-4-(4-morpholinocyclohexylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting trans4-morpholinocyclohexanamine for 1-isopropylpiperidin-4-amine in EXAMPLE41A.

EXAMPLE 205BTrans-2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 205A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) δ 9.17(d, 1H), 8.42 (d, 1H), 8.32 (dd, 1H), 8.00 (d, 1H),7.46 (d, 2H), 7.15 (t, 1H), 7.11 (d, 2H), 7.07 (d, 1H), 7.03(d, 1H),6.99 (d, 1H), 6.93 (dd, 1H), 6.81 (dd, 1H), 6.69 (d, 1H), 3.73-3.78 (m,4H), 3.43-3.50 (m, 1H), 3.15-3.21 (m, 4H), 2.84 (s, 2H), 2.50-2.54 (m,4H), 2.31 (t, 2H), 2.21-2.27 (m, 5H), 2.11 (d, 2H), 2.00 (s, 2H), 1.91(d, 2H), 1.36-1.43 (m, 4H), 1.28-1.34 (m, 2H), 0.96 (s, 6H).

EXAMPLE 2064-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(2-chlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 137 by replacingEXAMPLE 122C with EXAMPLE and EXAMPLE 111A with EXAMPLE 3I. ¹H NMR (400MHz, CH₂CD₂) δ 8.80 (s, 1H), 8.41 (d, 1H), 8.01 (d, 1H), 7.87 (d, 1H),7.55 (t, 2H), 7.29-7.37 (m, 4H), 7.17-7.28 (m, 4H), 7.10-7.15 (m, 2H),6.94 (d, 1H), 6.58 (d, 1H), 5.95 (s, 1H), 3.53-3.64 (m, 1H), 3.39 (q,1H), 3.01-3.12 (m, 4H), 2.77 (t, 2H), 2.38-2.46 (m, 2H), 2.15-2.31 (m,7H), 2.05 (d, 2H), 1.63-1.74 (m, 2H), 1.22 (d, 3H).

EXAMPLE 2072-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 207A 2-chloro 4-(medioxymethoxy)phenol

The title compound was prepared by substituting 2-chlorobenzene-1,4-diolfor EXAMPLE 158B in EXAMPLE 158C.

EXAMPLE 207B Ethyl2-((2-chloro-4-(methoxymethoxy)phenoxy)-4-fluorobenzoate

The title compound was prepared by substituting 207A for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 207C Ethyl2-(2-chloro-4-(methoxymethoxy)phenoxy)-4-fluorobenzoate

The title compound was prepared by substituting piperazine for EXAMPLE3F and EXAMPLE 207B for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 207D Ethyl2-(2-chloro-4-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorphenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 60D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 207C for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 207E2-(2-chloro-4-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 207D for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 207F2-(2-chloro-4-methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 207E for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 207G2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 207F for EXAMPLE158 in EXAMPLE 159. ¹H NMR (500 MHz, pyridine-d₅) δ 12.30 (br. s, 1H),9.29 (d, 1H), 8.49 (d, 1H), 8.40 (dd, 1H), 8.08 (d, 1H), 7.45 (d, 2H),7.09 (m, 3H), 7.01 (d, 1H), 6.93 (dd, 1H), 6.75 (dd, 1H), 6.58 (d, 1H),3.54 (m, 1H), 3.13 (m, 4H), 2.81 (s, 2H), 2.65 (m, 2H), 2.29 (m, 2H),2.21 (m, 4H), 2.16 (s, 3H), 2.07 (m, 2H), 1.96 (m, 4H), 1.66 (m, 2H),1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 2082-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 208A2-(2-chloro-4-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(4-methylpiperazin-1-ylamino)-3-nitrophenylsulfonyl)benzamide3

The title compound was prepared by substituting EXAMPLE 207E for EXAMPLE1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 208B2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 208A for EXAMPLE158E in EXAMPLE 159. ¹H NMR (500 MHz, pyridine-d₅) δ 12.33 (br. s, 1H),9.28 (m, 2H), 8.44 (dd, 1H), 8.07 (d, 1H), 7.76 (d, 1H), 7.45 (d, 2H),7.09 (m, 3H), 6.94 (dd, 1H), 6.75 (dd, 1H), 6.57 (d, 1H), 3.13 (m, 4H),2.94 (m, 4H), 2.81 (m, 4H), 2.29 (m, 2H), 2.19 (m, 10H), 1.99 (s, 2H),1.41 (t, 2H), 0.95 (m, 6H).

EXAMPLE 2094-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 209A 6-Fluoro-4-methoxy-1H-indole-2-carboxylic acid methyl ester

Sodium methoxide solution (25% by weight in methanol, 22.25 mL) andmethanol (52 mL) were added to a flask and cooled to −20° C. using anacetonitrile/dry ice bath. Ethyl 2-azidoacetate (25% by weight inethanol, 50.3 g) and 4-fluoro-2-methoxybenzaldehyde (5.00 g, dissolvedin ethyl 2-azidoacetate solution) were added drop-wise to the stirringsodium methoxide solution at −20° C. The solution was then stirred at−20° C. for 3.5 hours, then at 0° C. for one hour. The solution waspoured over ice, vacuum filtered, and washed with water. The filteredsolid was taken up in xylenes (100 mL), washed twice with brine, anddried using anhydrous sodium sulfate and filtered. In a separate flaskxylenes (50 mL) was brought to reflux. The xylene solution containingthe filtered material was added drop-wise to the refluxing xylenes. Thesolution was then refluxed for five hours, cooled, and placed in afreezer for 16 hours. The precipitate was filtered out. The volume ofthe filtrate was reduced on vacuum to generate a second crop ofprecipitate, which was washed with hexanes, then 5% ethyl acetate inhexanes and combined with material from the first filtration.

EXAMPLE 209B 6-Fluoro-4-methoxy-1H-indole-2-carboxylic acid

The title compound was prepared by substituting EXAMPLE 209A for EXAMPLE1E in EXAMPLE 1E.

EXAMPLE 209C 6-Fluoro-4-methoxy-1H-indole

EXAMPLE 209B (1775 mg) was dissolved in N-methylpyrrolidinone (75 mL),and copper powder (2157 mg) was added. The solution was stirred to keepthe copper powder suspended and the solution was split into ninemicrowave reactor vials, each containing a stir bar. Each vial washeated in a CEM Discover microwave reactor at 260° C. for 25 minuteswith stirring. The vials were combined, added to water, and extractedwith ethyl ether. The ether was washed with brine and dried on anhydroussodium sulfate. The solution was filtered and the filtrate wasconcentrated and purified by flash column chromatography on silica gelusing 10% ethyl acetate in hexanes.

EXAMPLE 209D 6-fluoro-1H-indol-4-ol

Aluminum chloride (727 mg) was added to dichloromethane (20 mL), themixture was cooled to 0° C., and benzylmercaptan (4512 mg) was added.EXAMPLE 209C (600 mg) dissolved in dichloromethane (5 mL) was addeddrop-wise. The solution was mixed for 30 minutes at 0° C.Benzylmercaptan (451 mg) and aluminum chloride (727 mg) were added, andthe solution was stirred for 75 minutes at 0° C. The reaction wasquenched by adding 1M aqueous HCl. The solution was extracted with ethylacetate, which was subsequently washed with brine and dried on anhydroussodium sulfate. After filtration, the filtrate was concentrated andpurified by flash column chromatography on silica gel using 5% ethylacetate in hexanes increasing to 20% ethyl acetate in hexanes andincreasing again to 50% ethyl acetate in hexanes.

EXAMPLE 209E 4-Fluoro-2-(6-fluoro-1H-indol-4-yloxy)-benzoic acid ethylester

The title compound was prepared by substituting EXAMPLE 209D for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 209F4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-(6-fluoro-1H-indol-4-yloxy)-benzoicacid ethyl ester

The title compound was prepared by substituting EXAMPLE 209E for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 209G4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]piperazin-1-yl}-2-(6-fluoro-1H-indol-4-yloxy)-benzoicacid

The title compound was prepared by substituting EXAMPLE 209E for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 209H4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 209G for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.14 (br s, 1H), 8.37 (d, 1H), 8.08 (d, 1H),7.68 (dd, 1H), 7.59 (d, 1H), 7.35 (d, 2H), 7.19 (t, 1H), 7.05 (d, 2H),6.97 (d, 1H), 6.78 (dd, 1H), 6.71 (dd, 1H), 6.34 (d, 1H), 6.26 (t, 1H),5.97 (dd, 1H), 3.74 (m, 1H), 3.18-3.09 (m, 2H), 3.05 (br s, 4H),2.83-2.70 (m, 2H), 2.74 (br s, 2H), 2.57 (s, 3H), 2.25-2.12 (m, 6H),2.09-2.01 (m, 2H), 1.96 (s, 2H), 1.72 (q, 2H), 1.39 (t, 2H), 0.93 (s,6H).

EXAMPLE 2104-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 209G for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.16 (br s, 1H), 8.39 (d, 1H), 7.64 (d, 1H),7.57 (d, 1H), 7.38-7.32 (d, 2H), 7.21 (t, 1H), 7.05 (d, 2H), 6.99 (d,1H), 6.80 (d, 1H), 6.73 (d, 1H), 6.35 (d, 1H), 6.26 (t, 2H), 6.00 (d,1H), 3.99-3.89 (m, 3H), 3.76 (m, 1H), 3.26 (m, 2H), 3.07 (m, 4H), 2.72(br s, 2H), 2.27-2.12 (m, 8H), 2.09-1.95 (m, 4H), 1.86-1.48 (m, 8H),1.39 (t, 2H), 0.93 (s, 6H).

EXAMPLE 2112-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideEXAMPLE 211A4-(4-methylpiperazin-1-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

The title compound was prepared by substituting4-methylpiperazin-1-amine for 3-(N-morpholinyl)-1-propylamine andEXAMPLE 131C for 4-Fluoro-3-nitrobenzenesulfonamide in EXAMPLE 4A.

EXAMPLE 211B2-(2-chloro-4-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(4-methylpiperazin-1-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 207E for EXAMPLE1F and EXAMPLE 211A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 211C2-(2-chloro-4-hydroxyphenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(4-methylpiperidin-1-yl)amino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 211B for EXAMPLE158E in EXAMPLE 159. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 9.87 (s,1H), 8.08 (d, 1H), 7.96 (s, 1H), 7.90 (dd, 1H), 7.54 (d, 1H), 7.48 (d,1H), 7.36 (d, 2H), 7.07 (d, 2H), 6.89 (d, 1H), 6.83 (d, 1H), 6.73 (dd,1H), 6.65 (dd, 1H), 6.21 (d, 1H), 3.07 (m, 4H), 2.90 (m, 6H), 2.76 (s,2H), 2.41 (s, 3H), 2.21 (m, 6H), 1.97 (s, 2H), 1.40 (t, 3H), 0.94 (s,6H).

EXAMPLE 2122-({1,3-bis[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 212A4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 202C for EXAMPLE1F and EXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 212B2-({1,3-bis[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide

EXAMPLE 212A (0.25 g) was dissolved in methanol (0.60 mL), to which wasadded 37% (wt) formaldehyde in water (0.22 mL) and 1-methylpiperazine10.33 mL). The reaction was heated at 60° for two hours, then cooled andconcentrated. The crude was purified by preparative HPLC using a C18column, 250×50 mm, 10μ, and eluting with a gradient of 20-100% CH₃CN vs.0.1% trifluoroacetic acid in water, giving the product as atrifuloroacetate salt. The salt was dissolved in dichloromethane (6 mL)and washed with 50% aqueous NaHCO₃. The organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated to give the title compound.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.68 (br t, 1H), 8.00 (s, 1H),7.82 (d, 1H), 7.38 (m, 3H), 7.25 (d, 1H), 7.08 (d, 2H), 6.87 (d, 1H),6.75 (d, 1H), 6.67 (m, 2H), 6.58 (s, 1H), 5.58 (d, 1H), 4.85 (s, 2H),3.40 (m, 4H), 3.20 (v br s, 4H), 3.05 (v br s, 4H), 2.79 (s, 2H), 2.60(v br s, 2H), 2.40 (br m, 6H), 2.20 (m, 21H), 2.09 (s, 3H), 1.98 (s,2H), 1.80 (m, 2H), 1.42 (t, 2H), 0.95 (s, 6H).

EXAMPLE 2134-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-({3-[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)benzamide

To EXAMPLE 212A (0.13 g) in methanol (0.30 mL) was added 37% (wt)formaldehyde in water (0.022 mL) and 1-methylpiperazine (0.035 mL). Thereaction was heated at 60° C. for 50 minutes, then it was cooled andconcentrated. The crude was purified by preparative HPLC using a C18column, 250×50 mm, 10μ, and eluting with a gradient of 20-100% CH₃CN vs.0.1% trifluoroacetic acid in water, giving the product as atrifluoroacetate salt. The salt was dissolved in dichloromethane (6 mL)and washed with 50% aqueous NaHCO₃. The organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated to give the title compound.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.23 (s, 1H), 8.68 (br t, 1H),7.96 (s, 1H), 7.79 (d, 1H), 7.38 (d, 2H), 7.31 (s, 1H), 7.17 (br d, 1H),7.08 (d, 2H), 6.75 (d, 2H), 6.66 (d, 1H), 6.60 (m, 2H), 5.65 (d, 1H),4.33 (br s, 2H), 3.40 (m, 4H), 3.20 (v br s, 4H), 3.03 (v br s, 4H),2.79 (s, 2H), 2.60 (v br s, 2H), 2.42 (br m, 2H), 2.20 (m, 15 H), 1.98(s, 2H), 1.83 (m, 2H), 1.42 (t, 2H), 0.95 (s, 6H).

EXAMPLE 2142-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonylcarbamoyl)pheonxy)-N,N-dimethylbenzamideEXAMPLE 214A methyl2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 3F for EXAMPLE1B in EXAMPLE 1C.

EXAMPLE 214B methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(2-(dimethylcarbamoyl)phenoxy)benzoate

The title compound was prepared by substituting EXAMPLE 214A for EXAMPLE1C and 2-hydroxy-N, N-dimethylbenzamide for EXAMPLE 1D in EXAMPLE 1E .

EXAMPLE 214C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(2-(dimethylcarbamoyl)phenoxy)benzoicacid

The title compound was prepared by susbtituting EXAMPLE 214B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 214D2-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonylcarbamoyl)pheonxy)-N,N-dimethylbenzamide

The title compound was prepared by substituting EXAMPLE 214C for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.35 (s, 1H), 8.07 (d, 1H), 7.72 (d, 1H), 7.61(d, 1H), 7.36 (d, 2H), 7.12 (m, 2H), 7.06 (d, 2H), 7.02 (d, 1H), 6.93(t, 1H), 6.68 (dd, 1H), 6.47 (d, 1H), 6.18 (d, 1H), 3.72 (m, 1H), 3.04(m, 4H), 2.95 (m, 2H), 2.86 (s, 3H), 2.75 (s, 2H), 2.70 (s, 3H), 2.42(m, 2H), 2.19 (m, 6H), 2.01 (m, 4H), 1.67 (m, 2H), 1.40 (t, 2H), 1.24(s, 3H), 0.94 (s, 6H).

EXAMPLE 2154-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-{[2-(trifluoromethyl)-1H-indol-4-yl]oxy}benzamideEXAMPLE 215A methyl 2-(3-amino-2-methylphenoxy)-4-fluorobenzoate

The title compound was prepared by substituting 3-amino-2-methylphenolfor 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 215B (E)-methyl2-(3-(1-chloro-2,2,2-trifluoroethylideneamino)-2-methylphenoxy)-4-fluorobenzoate

To a mixture of triethylamine (0.476 g) and triphenylphosphine (3.05 g)in CCL₄(10 mL) was added trifluoroacetic acid (0.477 g) dropwise at 0°C. The solution was stirred for 10 minutes. To this solution was addedEXAMPLE 215A (1.08 g) in CCl₄ (5 mL). The solution wsas heated underreflux for 3 hours. After cooling, the reaction mixture wasconcentrated, and diluted with 3:7 ethyl acetate/hexanes. The solid wasfiltered off, and the filtrate was concentrated. The residue waspurified by flash chromatography on silica gel eluting 1:10 ethylacetate/hexane to give the title compound.

EXAMPLE 215C (E)-methyl2-(2-(bromomethyl)-3-(1-chloro-2,2,2-trifluoroethylideneamino)phenoxy)-4-fluorobenzoate

A mixture of EXAMPLE 215B (1.4 g), N-bromosuccinimide (0.671 g), andbenzoyl peroxide (0.044 g) in CCl₄ (20 mL) was heated under reflux for 4hours. After cooling, the solid was filtered off. The filtrate was thenconcentrated. The residue was purified by flash chromatography on silicagel eluting 1:20 ethyl acetate/hexane to give the title compound.

EXAMPLE 215D methyl4-fluoro-2-(2-(trifluoromethyl)-1H-indol-4-yloxy)benzoate

Magnesium (0.081 g) in tetrahydrofuran (10 mL) was treated with EXAMPLE215C (1.3 g) in tetrahydrofuran (5 mL) drop-wise at 0° C. After theaddition was over, a couple of I₂ crystals were added to the reaction.After stirring for 2 hours, the magnesium started to disappear. Thereaction was stirred for another 6 hours at room temperature. Thereaction was quenched with saturated aqueous NH₄Cl, and extracted withethyl acetate. The aqueous layer was extracted with additional ethylacetate. The combined organic layers were washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was purified by flashchromatography on silica gel eluting with 1:4 ethyl acetate/hexanes togive the title compound.

EXAMPLE 215E methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(2-(trifluoromethyl)-1H-indol-4-yloxy)benzoate

The title compound was prepared by substituting EXAMPLE 215D for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 215F

A mixture of EXAMPLE 215E (0.13 g) and lithium iodide (0.534 g) inpyridine (2 mL) was heated in a CEM Discover microwave reactor (130° C.,30 minutes). The pyridine was removed under vacuum, and the residue waspartitioned between ethyl acetate and water. The aqueous layer wasextracted with additional ethyl acetate. The combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentrated.The residue was then purified by reverse phase Prep HPLC to give thedesired product.

EXAMPLE 215G4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-{[2-(trifluoromethyl)-1H-indol-4-yl]oxy}benzamide

The title compound was prepared by substituting EXAMPLE 215F for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 12.29 (s, 1H), 8.39 (d, 1H), 8.12 (d, 1H), 7.69(dd, 1H), 7.59 (d, 1H), 7.34 (d, 2H), 7.00-7.12 (m, 5H), 6.85 (s, 1H),6.71 (dd, 1H), 6.34 (d, 1H), 6.29 (d, 1H), 3.93 (dd, 1H), 3.06-3.09 (m,6H), 2.76 (s, 2H), 2.62-2.64 (m, 2H), 2.16-2.19 (m, 6H), 2.03-2.05 (m,2H), 1.96 (s, 2H), 1.79-1.82 (m, 2H), 1.66-1.68 (m, 2H), 1.49-1.57 (m,2H), 1.96 (t, 2H), 0.93 (s, 6H).

EXAMPLE 2162-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamideEXAMPLE 216A2-(2-chloro-4-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(1-tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 207E for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 216B2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 216A for EXAMPLE158E in EXAMPLE 159. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 9.83 (br,s, 1H), 8.47 (s, 1H), 8.17 (br. s, 1H), 7.76 (d, 1H), 7.50 (d, 1H), 7.35(d, 2H), 7.08 (m, 3H), 6.83 (m, 2H), 6.67 (m, 2H), 6.22 (d, 1H), 3.93(m, 2H), 3.81 (m, 1H), 3.07 (m, 6H), 2.75 (s, 2H), 2.19 (m, 8H), 1.97(s, 2H), 1.68 (m, 6H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 217(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-{[6-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamideEXAMPLE 217A 4-nitro-2-(trifluoromethyl)phenol

The title compound was prepared as described in EXAMPLE 200A byreplacing 2,3-difluoro-4-nitroanisole with2-tnfluoromethyl-4-nitroanisole.

EXAMPLE 217B 6-(trifluoromethyl)-1H-indol-5-ol

The title compound was prepared analogously to that of2-fluoro-4-nitrophenol in WO 02/12227 (page 78).

EXAMPLE 217C methyl4-fluoro-2-(6-(trifluoromethyl)-1H-indol-5-yloxy)benzoate

The title compound was prepared as described in EXAMPLE 3A by replacing2-methyl-5-indolol with EXAMPLE 217B.

EXAMPLE 217D methyl4-(piperazin-1-yl)-2-(6-(trifluoromethyl)-1H-indol-5-yloxy)benzoate

The title compound was prepared as described in EXAMPLE 3G by replacingEXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE 217C,respectively.

EXAMPLE 217E methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-(trifluoromethyl)-1H-indol-5-yloxy)benzoate

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLE 38F and EXAMPLE 38E with EXAMPLE 217D and EXAMPLE 60D,respectively.

EXAMPLE 217F4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-(trifluoromethyl)-1H-indol-5-yloxy)benzoicacid

The title compound was prepared as described in EXAMPLE 38 H byreplacing EXAMPLE 38G with EXAMPLE 217E.

EXAMPLE 217G(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-{[6-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 217F and EXAMPLE 3I,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.38 (s, 1H),8.43 (d, 1H), 8.09 (d, 1H), 7.77 (dd, 1H), 7.67 (s, 1H), 7.55 (m, 2H),7.33 (d, 2H), 7.02 (m, 4H), 6.67 (dd, 1H), 6.38 (s, 1H), 3.71 (m, 1H),3.05 (m, 7H), 2.72 (s, 3H), 2.25 (m, 7H), 1.98 (m, 5H), 1.72 (m, 3H),1.38 (t, 3H), 0.92 (s, 6H).

EXAMPLE 2184-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-{[6-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 217F and EXAMPLE 49C,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.42 (s, 1H),8.46 (d, 1H), 8.16 (d, 1H), 7.77 (dd, 1H), 7.70 (s, 1H), 7.56 (m, 2H),7.33 (m, 3H), 7.03 (m, 5H), 6.69 (dd, 1H), 6.40 (s, 1H), 6.14 (d, 1H),3.91 (m, 3H), 3.72 (m, 1H), 3.02 (m, 8H), 2.72 (s, 2H), 2.25 (m, 10H),1.95 (m, 4H), 1.48 (m, 5H), 0.92 (s, 6H).

EXAMPLE 2192-[(2-amino-1,3-thiazol-4-yl)methoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamideEXAMPLE 219A methyl 2-((2-aminothiazol-4-yl)methoxy)-4-fluorobenzoate

A mixture of methyl 4-fluoro-2-hydroxybenzoate (552 mg),4-(chloromethyl)thiazol-2-amine hydrochloric acid (600 mg) and Cs₂CO₃(2.64 g) in 15 mL. N,N-dimethylformamide was stirred at room temperaturefor 24 hours. Water was added and the mixture was extracted with ethylacetate (2×), washed with water (2×) and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica gelusing 10-50% ethyl acetate in hexanes as eluent.

EXAMPLE 219B methyl2-((2-aminothiazol-4-yl)methoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 219A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 219C methyl2-((2-(tert-butoxycarbonylamino)thiazol-4-yl)methoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

To a solution of EXAMPLE 219B (280 mg), 4-(dimethylamino)pyridine (2.94mg), triethylamine (81 μL) in 10 mL tetrahydrofuran at room temperaturewas added a solution of di-tert-butyl dicarbonate (134 μL) in 3 mLtetrahydrofuran via a cannula. The mixture was stirred at roomtemperature overnight, and partitioned between water and ethyl acetate.The aqueous phase was extracted with ethyl acetate and the combinedorganics were washed with brine and dried over MgSO₄, filtered andconcentrated. The oil residue was chromatographed on silica gel with25-60% ethyl acetate in hexanes.

EXAMPLE 219D2-((2-(tert-butoxycarbonylamino)thiazol-4-yl)methoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 219C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 219E tert-butyl4-((5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)phenylsulfonylcarbamoyl)phenoxy)methyl)thiazol-2ol-2-ylcarbamate

The title compound was prepared by substituting EXAMPLE 219D for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G respectively in EXAMPLE 1H.

EXAMPLE 219F2-((2-aminothiazol-4-yl)methoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)phenylsulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 219E for EXAMPLE 1A inEXAMPLE 1B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 0.96 (s, 6H)1.36-1.78 (m, 8H) 1.99 (m, 2H) 2.14-2.31 (m, 7H) 2.40-2.64 (m, 3H) 2.78(m, 2H) 2.92 (d, 2H) 3.16-3.43 (m, 10H) 3.75 (m, 1H) 3.84-3.96 (m, 2H)5.01 (s, 2H) 6.51 (d, 1H) 6.57 (s, 1H) 6.63 (s, 1H) 6.93 (s, 2H) 7.06(d, 2H) 7.28 (d, 1H) 7.37 (d, 2H) 7.45 (d, 1H) 7.93 (dd, 1H) 8.28 (d,1H) 8.62 (d, 1H).

EXAMPLE 2204-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 200F and EXAMPLE 184A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.72 (s, 1H),9.14 (s, 1H), 8.47 (d, 1H), 7.82 (m, 1H), 7.54 (dd, 2H), 7.41 (t, 1H),7.34 (d, 2H), 7.04 (d, 1H), 6.92 (d, 1H), 6.66 (d, 1H), 6.42 (d, 1H),6.21 (s, 1H), 2.98 (m, 11H), 2.73 (s, 2H), 2.40 (s, 4H), 2.17 (m, 7H),1.95 (s, 3H), 1.38 (t, 2H), 0.93 (s, 6H).

EXAMPLE 2214-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.19 (s, 1H), 9.17 (s, 1H), 8.52 (d, 1H), 7.89(dd, 1H), 7.59 (d.1H), 7.53 (d, 1H), 7.34 (m, 4H), 7.23 (d, 1H), 7.04(d, 2H), 6.62 (dd, 1H), 6.39 (m, 1H), 6.07 (m, 1H), 2.94 (m, 10H), 2.71(s, 2H), 2.36 (s, 3H), 2.15 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92(m, 6H).

EXAMPLE 222 tert-butyl4-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)amino]carbonyl}phenoxy)methyl]-1,3-thiazol-2-ylcarbamate

The title compound was prepared by substituting EXAMPLE 219D for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G respectivelyin EXAMPLE 1H. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 0.96 (s, 6H) 1.37-1.54 (m, 12H) 1.60-1.79(m, 2H) 1.97-2.08 (m, 3H) 2.15-2.30 (m, 7H) 2.38 (s, 3H) 2.78 (s, 2H)2.91 (d, 2H) 3.17-3.26 (m, 5H) 3.69-3.84 (m, 1H), 5.08 (s, 2H) 6.48 (d,1H) 6.53 (s, 1H) 7.07 (d, 2H) 7.17 (s, 1H) 7.23 (d, 1H) 7.37 (d, 2H)7.43 (d, 1H) 7.90 (dd, 1H) 8.22 (d, 1H) 8.58 (d, 1H) 10.39 (s, 1H),11.35 (s, 1H).

EXAMPLE 2232-[(2-amino-1,3-thiazol-4-yl)methoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 222 for EXAMPLE1A in EXAMPLE 1B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 0.96 (s, 6H)1.42 (t, 2H) 1.59-1.76 (m, 2H) 1.92-2.06 (m, 3H) 2.16-2.42 (m, 11H) 2.78(s, 4H) 3.20-3.26 (m, 5H) 3.67-3.82 (m, 1H) 4.99 (s, 2H) 6.50 (d, 1H)6.55 (s, 1H) 6.62 (s, 1H) 6.91 (s, 2H) 7.08 (d, 2H) 7.26 (d, 1H) 7.37(d, 2H) 7.45 (d, 1H) 7.93 (dd, 1H) 8.24 (d, 1H) 8.60 (d, 1H).

EXAMPLE 2242-[3-(acetylamino)phenoxy]-(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 224A methyl2-(3-acetamidophenoxy-(4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting 3-acetamidophenol forEXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 224B2-(3-acetamidophenoxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 224A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 224C2-[3-(acetylamino)phenoxy]-(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 224B for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.48 (s,1H), 9.89 (s, 1H), 8.59 (m, 1H), 8.50 (d, 1H), 7.71 (dd, 1H), 7.47 (m,6H), 7.36 (m, 2H), 7.24 (m, 2H), 7.14 (m, 3H), 6.75 (dd, 1H), 6.50 (dd,1H), 6.39 (d, 1H), 3.86 (dd, 2H), 3.37 (m, 2H), 3.30 (m, 6H), 3.16 (m,4H), 2.35 (s, 4H), 2.00 (s, 3H), 1.89 (m, 1H), 1.63 (dd, 2H), 1.27 (m,2H).

EXAMPLE 2252-[3-(acetylamino)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 224B for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 9.86 (s, 1H), 8.45 (d, 1H), 8.15 (d, 1H), 7.70(dd, 1H), 7.54 (d, 1H), 7.36 (d, 2H), 7.29 (d, 1H), 7.09 (m, 4H), 6.98(m, 1H), 6.70 (dd, 1H), 6.45 (dd, 1H), 6.33 (d, 1H), 3.95 (dd, 2H), 3.83(m, 1H), 3.36 (m, 3H), 3.24 (m, 2H), 3.11 (m, 4H), 2.77 (m, 4H), 2.17(m, 8H), 1.98 (m, 5H), 1.66 (m, 6H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 2262-[(2-chlorophenyl)amino]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamideEXAMPLE 226A methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(2-chlorophenylamino)benzoate

A solution of EXAMPLE 214A (500 mg), cesium carbonate (429 mg),palladium(II) acetate (21 mg), rac-BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (58.5 mg) and toluene (6.4mL) was degassed with N₂. The solution was stirred at 115° C. for 5minutes. After cooling to room temperature, 2-chloroaniline (144 mg) wasadded and the reaction mixture was degassed again with N₂ and wasstirred at 115° C. for 45 minutes. The solution was cooled to roomtemperature, diluted with ethyl acetate and was washed with water andbrine, dried (MgSO₄), filtered and concentrated. The crude material waspurified by flash chromatography on silica gel, eluting withdichloromethane/1% methanol.

EXAMPLE 226B4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(2-chlorophenylamino)benzoicacid

The title compound was prepared by substituting EXAMPLE 226A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 226C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(2-chlorophenylamino)-N-(3-nitro-4-(1-tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 226B for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.11 (br s, 1H), 9.16 (br s, 1H), 8.53 (d, 1H),7.97-8.20 (m, 1H), 7.93 (d, 1H), 7.81 (d, 1H), 7.47 (d, 1H), 7.42 (dd,1H), 7.36 (d, 2H), 7.22 (t, 1H), 7.15 (d, 1H), 7.07 (d, 2H), 6.89 (t,1H), 6.52 (d, 1H), 6.34 (dd, 1H), 3.96 (d, 2H), 3.46-3.78 (m, 2H),3.33-3.40 (m, 2H), 3.23-3.28 (m, 2H), 2.96-3.14 (m, 6H), 2.13-2.31 (m,8H), 1.98 (br s, 6H), 1.65 (br s, 4H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 2274-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-methoxy-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamideEXAMPLE 227A 6-Methoxy-1H-indol-5-ol

5-(benzyloxy)-6-methoxy-1H-indole (3.00 g) was added to methanol (100mL) and ethyl acetate (100 mL) in a pressure bottle. Palladium hydroxideon carbon (0.832 g,) was added and the solution was shaken under 30 psiof hydrogen at room temperature for 40 minutes. The mixture was filteredthrough a nylon membrane, the solvent removed under vacuum, the residuetaken up in ethyl acetate, the solution was filtered over a pad ofsilica gel, and the solvent was removed from the filtrate under vacuum.

EXAMPLE 227B 4-Fluoro-2-(6-methoxy-1H-indol-5-yloxy)-benzoic acid methylester

The title compound was prepared by substituting methyl2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and EXAMPLE 227A for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 227C 2-(6-Methoxy-1H-indol-5-yloxy)-4-piperazin-1-yl-benzoicacid methyl ester

The title compound was prepared by substituting piperazine for EXAMPLE3F and EXAMPLE 227B for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 227D4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-(6-methoxy-1H-indol-5-yloxy)-benzoicacid methyl ester

The title compound was prepared by substituting EXAMPLE 60D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 227C for tert-butylpiperazrae-1-carboxylate in EXAMPLE 1A.

EXAMPLE 227E4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-(6-methoxy-1H-indol-5-yloxy)-benzoicacid

The title compound was prepared by substituting EXAMPLE 227D for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 227F4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-methoxy-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 227E for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.02 (br s, 1H), 8.60 (d, 1H), 8.25 (d, 1H),7.89 (dd, 1H), 7.54 (d, 1H), 7.33 (d, 2H), 7.29-7.26 (m, 2H), 7.21 (d,1H), 7.09 (s, 1H), 7.04 (d, 2H), 6.59 (dd, 1H), 6.36 (t, 1H), 6.03 (d,1H), 3.96-3.87 (m, 3H), 3.74 (s, 3H), 3.73 (m, 1H), 2.97 (m, 8H), 2.70(br s, 2H), 2.13 (br s, 8H), 2.05-1.92 (m, 4H), 1.74 (m, 2H), 1.63 (m,2H), 1.49 (m, 2H), 1.37 (t, 2H), 0.92 (s, 6H).

EXAMPLE 2292-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 229A methyl 2-(2-aminobenzo[d]thiazol-6-yloxy)-4-fluorobenzoate

The title compound was prepared by substituting2-aminobenzo[d]thiazol-6-ol for 2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 229B methyl2-(2-aminobenzo[d]thiazol-6-yloxy)-4(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 229A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 229C methyl2-(2-(tert-butoxycarbonylamino)benzo[d]thiazol-6-yl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 229B for EXAMPLE219B in EXAMPLE 219C.

EXAMPLE 229D2-(2-(tert-butoxycarbonylamino)benzo[d]thiazol-6-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 229C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 229E tert-butyl6-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonylcarbamoyl)phenoxy)benzo[d]thiazol-2-ylcarbamate

The title compound was prepared by substituting EXAMPLE 229D for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G respectivelyin EXAMPLE 1H.

EXAMPLE 229F2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 229E for EXAMPLE1A in EXAMPLE 1B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 0.93 (s, 6H)1.39 (t, 2H) 1.62-1.80 (m, 2H) 1.91-2.24 (m, 10H) 2.50-2.62 (m, 4H) 2.74(s, 4H) 2.97-3.18 (m, 5H) 3.66-3.82 (m, 1H) 6.24 (d, 1H) 6.64 (dd, 1H)6.75 (dd, 1H) 6.92 (d, 1H) 7.01-7.12 (m, 3H) 7.20 (d, 1H) 7.31 (s, 2H)7.35 (d, 2H) 7.52 (d, 1H) 7.61-7.71 (m, 1H) 8.09 (d, 1H) 8.44 (d, 1H).

EXAMPLE 2302-[(2-chlorophenyl)amino]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 226B for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.11 (br s, 1H), 8.53 (d, 1H), 7.02 (br s, 1H),7.94 (dd, 1H), 7.81 (d, 1H), 7.46 (dd, 1H), 7.42 (dd, 1H), 7.36 (d, 2H),7.18-7.25 (m, 1H), 7.14 (d, 1H), 7.07 (d, 2H), 6.85-6.92 (m, 1H), 6.52(d, 1H), 6.33 (dd, 1H), 3.88 (br s, 1H), 3.01-3.09 (m, 7H), 2.66-2.83(m, 6H), 2.07-2.32 (m, 8H), 1.97 (br s, 3H), 1.78 (br s, 2H), 1.41 (t,2H), 0.94 (s, 6H).

EXAMPLE 231 tert-butyl5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]amino}carbonyl)phenoxy]-1H-indole-1-carboxylateEXAMPLE 231A ethyl 2-(1H-indol-5-yloxy)-4-fluorobenzoate

The title compound was prepared by substituting 5-hydroxyindole for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 231B ethyl2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 231A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 231C2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 231B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 231D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 231C for EXAMPLE1F and EXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H, except 2-10% methanolinCH₂C₂ was used for the chromatography.

EXAMPLE 231E tert-butyl5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]amino}carbonyl)phenoxy]-1H-indole-1-carboxylatebis(2,2,2-trifluoroacetate)

The title compound was prepared by substituting EXAMPLE 231D for EXAMPLE202D in EXAMPLE 202E. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.63 (vbr s, 1H), 9.40 (v br s, 2H), 8.61 (br t, 1H), 8.33 (d, 1H), 8.00 (d,1H), 7.85 (dd, 1H), 7.70 (d, 1H), 7.54 (d, 1H), 7.40 (d, 2H), 7.10 (m,4H), 6.97 (dd, 1H), 6.76 (dd, 1H), 6.43 (d, 1H), 6.33 (d, 1H), 3.60,3.50, 3.30 (all v br m, total 10H), 3.10 (br m, 4H), 2.79 2.77 (both s,total 6H), 2.20 (br m, 2H), 2.04 (s, 2H), 1.85 (br m, 2H), 1.66 (s, 9H), 1.45 (br t, 2H), 0.95 (s, 6H).

EXAMPLE 2322-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamideEXAMPLE 232A tert-butyl6-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)phenylsulfonylcarbamoyl)phenoxy)benzo[d]thiazol-2-ylcarbamate

The title compound was prepared by substituting EXAMPLE 229D for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G respectivelyin EXAMPLE 1H.

EXAMPLE 232B2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 232A for EXAMPLE1A in EXAMPLE 1B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 0.95 (s, 6H)1.44 (br. s, 2H) 1.61-1.89 (m, 3H) 1.90-2.12 (m, 5H) 2.13-2.32 (m, 4H)2.36-2.63 (m, 2H) 2.97 -3.78 (m, 16H) 4.01 (dd, 2H) 6.30 (s, 1H) 6.72(d, 1H) 6.84 (d, 1H) 7.11 (m, 3H) 7.18-7.32 (m, 2H) 7.33-7.55 (m, 5H)7.68-7.89 (m, 1H) 8.17 (d, 1H) 8.57 (d, 1H) 9.25 (br. s, 1H) 11.62 (br.s, 1H).

EXAMPLE 2334-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared by susbtituting EXAMPLE 154E for EXAMPLE122C and EXAMPLE 254A for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.20 (br s, 1H), 8.62 (br t, 1H), 8.57 (d, 1H),7.83 (dd, 1H), 7.75 (s, 1H), 7.51 (d, 1H), 7.37 (dd, 1H), 7.34 (m, 3H),7.26 (d, 1H), 7.08 (d, 1H), 7.04 (d, 2H), 6.63 (dd, 1H), 6.40 (s, 1H),6.09 (s, 1H), 3.43 (dd, 2H), 3.18 (br m, 2H), 3.04 (br m, 4H), 2.95 (s,2H), 2.70 (s, 2H), 2.55 (t, 2H), 2.45 (t, 2H), 2.17 (br m, 6H), 1.95 (s,2H), 1.79 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 234Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE122C and EXAMPLE 205A for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.20 (s, 1H), 8.54 (s, 1H), 8.17 (br d, 1H),7.84 (d, 1H), 7.52 (d, 1H), 7.34 (m, 4H), 7.24 (br d, 1H), 7.11 (br d,1H), 7.04 (d, 2H), 6.64 (d, 1H), 6.40 (s, 1H), 6.09 (s, 1H), 3.62 (br m,4H), 3.58 (v br s, 1H), 3.00 (br m, 4H), 2.73 (s, 2H), 2.65 (br m, 4H),2.47 (v br s, 1H), 2.18 (br m, 6H), 2.06 (br m, 2H), 1.93 (br m, 4H),1.40 (m, 6H), 0.92 (s, 6H).

EXAMPLE 235Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 200F for EXAMPLE122C and EXAMPLE 205A for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.72 (s, 1H), 8.46 (s, 1H), 8.15 (br d, 1H),7.78 (d, 1H), 7.52 (d, 1H), 7.40 (dd, 1H), 7.34 (d, 2H), 7.06 (br d,1H), 7.05 (d, 2H), 6.91 (br d, 1H), 6.66 (br d, 1H), 6.40 (s, 1H), 6.25(d, 1H), 3.62 (br m, 4H), 3.58 (v br s, 1H), 3.00 (br m, 4H), 2.73 (s,2H), 2.65 (br m, 4H), 2.47 (v br s, 1H), 2.18 (br m, 6H), 2.06 (br m,2H), 1.93 (br m, 4H), 1.40 (m, 6H), 0.92 (s, 6H).

EXAMPLE 2364-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 236A tert-butyl 1-(cyclopropylmethyl)piperidin-4-ylcarbamate

The title compound was prepared by substituting cyclopropanecarbaldehydefor 4′-chlorobiphenyl-2-carboxaldehyde and tert-butylpiperidin-4-ylcarbamate for tert-butyl piperazine-1-carboxylate inEXAMPLE 1A.

EXAMPLE 236B 1-(cyclopropylmethyl)piperidin-4-aminebis(2,2,2-trifluoroacetate)

The title compound was prepared by substituting EXAMPLE 236A for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 236C4-(1-(cyclopropylmethyl)piperidin-4-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 236B for4-(1-isopropylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide in EXAMPLE41A.

EXAMPLE 236D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 236C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) δ 12.39 (s, 1H), 9.31 (d, 1H), 8.49 (d, 1H), 8.45 (dd, 1H),8.15 (d, 1H), 7.47-7.52 (m, 3H), 7.41-7.45 (m, 3H), 7.04 (d, 2H), 6.98(d, 1H), 6.71 (dd, 1H), 6.57 (dd, 2H), 3.48-3.55 (m, 1H), 3.01-3.07 (m,4H), 2.86 (d, 2H), 2.74 (s, 2H), 2.21-2.26 (m, 2H), 2.19 (d, 4H),2.07-2.13 (m, 4H), 1.93-2.00 (m, 4H), 1.63-1.71 (m, 2H), 1.38 (t, 2H),0.93 (s, 6H), 0.84-0.91 (m, 1H), 0.45-0.49 (m, 2H), 0.11 (q, 2H).

EXAMPLE 2374-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-[(6,7-difluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 200F for EXAMPLE1F and EXAMPLE 236C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) δ 13.12 (s, 1H), 9.29 (d, 1H), 8.49 (d, 1H), 8.46 (dd, 1H),8.11 (d, 1H), 7.42 (d, 2H), 7.19 (s, 1H), 7.04 (d, 2H), 6.98 (d, 1H),6.75 (dd, 1H), 6.66 (d, 1H), 6.51-6.54 (m, 1H), 3.50-3.55 (m, 1H),3.07-3.13 (m, 4H), 2.83-2.87 (m, 2H), 2.76 (s, 2H), 2.25 (t, 2H),2.11-2.23 (s, 8H), 1.93-2.00 (m, 4H), 1.63-1.71 (m, 2H), 1.38 (t, 2H),0.92 (s, 6H), 0.84-0.90 (m, 1H), 0.44-0.49 (m, 2H), 0.08-0.12 (m, 2H).

EXAMPLE 2384-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.23 (s,1H), 8.63 (t, 1H), 8.60 (d, 1H), 7.87 (dd, 1H), 7.51 (d, 1H), 7.38 (t,1H), 7.30-7.34 (m, 4H), 7.17 (d, 1H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.41(s, 1H), 6.09 (s, 1H), 3.85 (dd, 2H), 3.26 (t, 2H), 3.03 (s, 4H), 2.74(s, 2H), 2.12-2.19 (m, 6H), 1.94 (s, 2H), 1.87-1.90 (m, 1H), 1.62 (d,2H), 1.38 (t, 2H), 1.22-1.30 (m, 2H), 0.92 (s, 6H).

EXAMPLE 2394-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 200F for EXAMPLE122C and EXAMPLE 254A for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.68 (br s, 1H), 8.70 (v br s, 1H), 8.46 (s,1H), 7.74 (s, 1H), 7.73 (br s, 1H), 7.52 (d, 1H), 7.37 (dd, 1H), 7.34(d, 2H), 7.05 (d, 2H), 7.95 (v br s, 1H), 6.83 (v br s, 1H), 6.67 (dd,1H), 6.39 (s, 1H), 6.25 (d, 1H), 3.44 (q, 2H), 3.18 (br m, 2H), 3.04 (brm, 4H), 2.97 (s, 2H), 2.73 (s, 2H), 2.57 (t, 2H), 2.47 (t, 2H), 2.18 (brm, 6H), 1.95 (s, 2H), 1.88 (m, 2H), 1.37 (t, 2H), 0.91 (s, 6H).

EXAMPLE 2404-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 240AN-(4-chloro-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE122C and 4-chloro-3-nitrobenzenesulfonamide for EXAMPLE 11A in EXAMPLE137.

EXAMPLE 240B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

EXAMPLE 240A (150 mg) was dissolved in dioxane (1.8 mL), then2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol (35 mg) and triethylamine(0.078 mL) were added. The reaction was heated at 110° C. for 20 hours.The reaction was concentrated and the crude was purified by preparativeHPLC using a C18 column, 250×50 mm, 10μ, and eluting with a gradient of20-100% CH₃CN vs. 0.1% trifluoroacetic acid in water, giving the productas a trifluoroacetate salt. The salt was dissolved in dichloromethane (6mL) and washed with 50% aqueous NaHCO₃. The organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated to give the title compound.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.23 (s, 1H), 8.60 (d, 1H),8.58 (d, 1H), 7.84 (dd, 1H), 7.52 (d, 1H), 7.39 (dd, 1H), 7.33 (m, 4H),7.29 (d, 1H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.42 (s, 1H), 6.08 (s, 1H),5.03 (t, 1H), 3.85 (m, 2H), 3.74 (m, 1H), 3.63 (m, 1H), 3.57 (m, 1H),3.26 (dd, 2H), 3.02 (br m, 4H), 2.73 (s, 2H), 2.18 (br m, 6H), 1.95 (s,2H), 1.94 (m, 1H), 1.61 (br m, 2H), 1.38 (m, 3H), 1.30 (m, 1H), 0.92 (s,6H).

EXAMPLE 2414-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino-3-nitrophenyl]sulfonyl}benzamideEXAMPLE 241A4-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)methanol for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.

EXAMPLE 241B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino-3-nitrophenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 241A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.22 (s, 2H), 9.10 (t, 1H), 8.59 (d, 1H), 7.87(dd, 1H), 7.51 (d, 1H), 7.30-7.39 (m, 5H), 7.24 (d, 1H), 7.02-7.05 (m,2H), 6.68 (dd, 1H), 6.41 (s, 1H), 6.08 (s, 1H), 5.22 (t, 1H), 3.51-3.62(m, 6H), 3.41 (d, 2H), 3.03 (s, 4H), 2.73 (s, 2H), 2.09-2.18 (m, 6H),1.95 (s, 2H), 1.45-1.51 (m, 4H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 2422-[(6-chloro-1H-indol-5-yl)oxy]4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamideEXAMPLE 242A ethyl 2-(4-amino-2-chlorophenoxy)-4-fluorobenzoate

To a solution of ethyl 2,4-difluorobenzoate (6.48 g) and4-amino-2-chlorophenol (5.0 g) in diglyme (40 mL) was added K₃PO₄ (7.39g). The mixture was stirred at 110° C. overnight. The mixture wasdiluted with ethyl acetate (300 mL) and washed with water, brine anddried over Na₂SO₄. The mixture was filtered, and the solvent wasevaporated and the residue was loaded on a column and eluted with 10%ethyl acetate in hexane to give the product.

EXAMPLE 242B ethyl 2-(4-amino-2-chloro-5-iodophenoxy)-4-fluorobenzoate

To a solution of EXAMPLE 242A (8.15 g) is dichloromethane (60 mL) wasadded bis(pyridine)iodonium tetrafluoroborate (9.79 g). The mixture wasstirred at room temperature for 4 hours. The mixture was diluted withethyl acetate (200 mL) and washed with aqueous Na₂S₂O₃, water, brine anddried over Na₂SO₄. The mixture was filtered, and the solvent wasevaporated and the residue was loaded on a column and eluted with 10%ethyl acetate in hexane to give the pure product.

EXAMPLE 242C ethyl2-(4-amino-2-chloro-5-((trimethylsilyl)ethynyl)phenoxy)-4-fluorobenzoate

To a mixture of EXAMPLE 242B (3.0 g),bis(triphenylphosphine)palladium(II) dichloride (242 mg), CuI (66 mg) intriethylamine (30 mL) was added trimethylsilylacetylene (2.2 g). Themixture was stirred at room temperature overnight. The mixture wasdiluted with ethyl acetate (200 mL) and washed with aqueous NH₄Cl,water, brine and dried over Na₂SO₄. The mixture was filtered, and thesolvent was evaporated and the residue was loaded on a column and elutedwith 10% ethyl acetate in hexane to give the pure product.

EXAMPLE 242D ethyl2-(4-amino-2-chloro-5-ethynylphenoxy)-4-fluorobenzoate

To a solution of EXAMPLE 242C (2.69 g) in methanol (20 mL) was added CsF(5 g). The mixture was stirred at room temperature overnight. Thesolvent was evaporated and the residue was dissolved in ethyl acetate(200 mL) and washed with water, brine and dried over Na₂SO₄. The mixturewas filtered, and the solvent was evaporated.

EXAMPLE 242E ethyl 2-(6-chloro-1H-indol-5-yloxy)-4-fluorobenzoate

To a solution of EXAMPLE 242D (1.0 g) in ethanol (20 mL) was addedNaAuCl₄ 2H₂O (60 mg). The mixture was stirred at room temperature for 4hours. The mixture was diluted with ethyl acetate (200 mL) and washedwith water, brine and dried over Na₂SO₄. The mixture was filtered, andthe solvent was evaporated and the residue was loaded on a column andeluted with 10% ethyl acetate in hexane to give the pure product.

EXAMPLE 242F ethyl2-(6-chloro-1H-indol-5-yloxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 3G by replacingEXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE 242E respectively.

EXAMPLE 242G ethyl2-(6-chloro-1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLE 38F and EXAMPLE 38E with EXAMPLE 242F and EXAMPLE 60D.

EXAMPLE 242H2-(6-chloro-1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 38H by replacingEXAMPLE 38G with EXAMPLE 242G.

EXAMPLE 242I2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 242H and EXAMPLE 49C,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.20 (s, 1H),8.52 (m, 1H), 8.18 (d, 1H), 7.83 (dd, 1H), 7.53 (m, 2H), 7.40 (m, 1H),7.33 (d, 3H), 7.18 (m, 1H), 7.04 (m, 4H), 6.62 (m, 1H), 6.38 (s, 1H),6.01 (d, 1H), 3.92 (m, 2H), 3.77 (m, 1H), 3.13 (m, 8H), 2.71 (s, 2H),2.24 (m, 8H), 1.95 (m, 6H), 1.52 (m, 6H), 0.94 (s, 6H).

EXAMPLE 2434-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F with EXAMPLE 200F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.75 (s, 1H), 8.59 (t, 1H), 8.53 (d, 1H), 7.82 (dd, 1H), 7.49 (d, 1H),7.41 (m, 1H), 7.34 (d, 3H), 7.12 (d, 1H), 7.04 (d, 2H), 6.98 (d, 1H),6.69 (dd, 1H), 6.43 (d, 1H), 6.24 (d, 1H), 3.85 (m, 2H), 3.07 (m, 5H),2.74 (m, 2H), 2.23 (m, 6H), 1.92 (m, 5H), 1.60 (m, 3H), 1.30 (m, 4H),0.94 (s, 6H).

EXAMPLE 2442-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 242H and EXAMPLE 184A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.24 (s, 1H),9.19 (s, 1H), 8.52 (d, 1H), 7.88 (dd, 1H), 7.56 (m, 3H), 7.42 (t, 1H),7.31 (m, 3H), 7.03 (d, 2H), 6.63 (dd, 1H), 6.41 (s, 1H), 5.98 (d, 1H),2.94 (m, 10H), 2.70 (s, 3H), 2.37 (m, 3H), 2.14 (m, 6H), 1.94 (s, 2H),1.37 (t, 2H), 0.91 (s, 6H).

EXAMPLE 2454-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamideEXAMPLE 245A tert-butyl 1-(thiazol-4-ylmethyl)piperidin-4-ylcarbamate

The title compound was prepared by substituting thiazole-4-carbaldehyde4′-chlorobiphenyl-2-carbaldehyde and tert-butylpiperidin-4-ylcarbamatefor tert-butyl piperazine-1-carboxylate in EXAMPLE 1A

EXAMPLE 245B

The title compound was prepared by substituting EXAMPLE 245A for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 245C3-nitro-4-1-(thiazol-4-ylmethyl)piperidin-4-ylamino)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 243B for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.

EXAMPLE 245D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 245C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.16 (s, 1H), 9.08 (s, 1H), 8.20 (s, 1H), 7.91(s, 1H), 7.82 (d, 1H), 7.29-7.34 (m, 4H), 7.18 (d, 1H), 7.15 (m, 1H),7.04 (d, 2H), 6.60 (dd, 1H), 6.37 (s, 1H), 6.08 (s, 1H), 4.28 (s, 2H),2.90-2.98 (m, 8H), 2.72 (s, 2H), 2.14-2.17 (m, 6H), 2.01 (m, 2H), 1.95(s, 2H), 1.53-1.55 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 2462-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 8.60 (t, 1H),8.42 (d, 1H), 7.71 (dd, 1H), 7.51 (d, 1H), 7.36 (d, 2H), 7.19 (t, 1H),7.10 (d, 1H), 7.07 (d, 2H), 6.93 (dd, 1H), 6.79 (dd, 1H), 6.72 (dd, 1H),6.69 (t, 1H), 6.47 (d, 1H), 3.87 (dd, 2H), 3.21-3.32 (m, 4H), 3.20 (s,4H), 2.81 (s, 2H), 2.27 (s, 4H), 2.16 (br s, 2H), 1.90-1.98 (m, 3H),1.63-1.66 (m, 2H), 1.41 (t, 2H), 1.27-1.30 (m, 2H), 0.94 (s, 6H).

EXAMPLE 2472-(4-amino-3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 40C for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.12 (s,1H), 8.50 (d, 2H), 7.84 (dd, 1H), 7.58 (d, 1H), 7.32-7.34 (m, 2H), 7.28(d, 1H), 7.15 (d, 1H), 7.10 (d, 1H), 7.04 (d, 2H), 6.58 (dd, 1H), 6.34(s, 1H), 6.07 (d, 1H), 3.63-3.70 (m, 6H), 2.96 (s, 4H), 2.71 (s, 2H),2.12-2.16 (m, 6H), 1.95 (s, 2H), 1.72-1.76 (m, 2H), 1.55-1.60 (m, 2H),1.38 (t, 2H), 0.94 (s, 6H).

EXAMPLE 248N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 191A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.12 (s, 1H), 8.50 (d, 1H), 7.84 (dd, 1H),7.32-7.34 (m, 3H), 7.28 (d, 1H), 7.15 (d, 1H), 7.11 (d, 1H), 7.04 (d,2H), 6.58 (dd, 1H), 6.34 (s, 1H), 6.07 (d, 1H), 3.85-3.89 (m, 4H),3.61-3.63 (m, 2H), 3.66-3.69 (m, 4H), 3.48-3.51 (m, 2H), 2.96 (s, 4H),2.71 (s, 2H), 2.14-2.18 (m, 6H), 1.95 (s, 2H), 1.72-1.76 (m, 2H),1.57-1.70 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 2494-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(3S,4R)-3-hydroxy-1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 249A

A mixture of tert-butyl(3S,4R)-1-benzyl-3-hydroxypiperidin-4-ylcarbamate (0.42 g) and palladiumhydroxide on carbon (0.095 g) in ethanol (15 mL) was hydrogenated with aballoon of H₂. The reaction mixture was stirred for 16 hours. The solidwas filtered off, and the filtrate was concentrated to give the titlecompound.

EXAMPLE 249B tert-butyl(3R,4S)-3-hydroxy-1-(thiazol-4-ylmethyl)piperidin-4-ylcarbamate

The title compound was prepared by substituting thiazole-4-carhaldehydefor 4-chlorobiphenyl-2-carbaldehyde and EXAMPLE 249A fortert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 249C (3R,4S)-4-amino-1-(thiazol-4-ylmethyl)piperidin-3-ol

The title compound was prepared by substituting EXAMPLE 249B for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 249D4-((3R,4S)-3-hydroxy-1-(thiazol-4-ylmethyl)piperidin-4-ymamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 249C for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.

EXAMPLE 249E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(3R,4S)-3-hydroxy-1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 249D for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.20 (s, 1H), 8.64 (t, 1H), 9.07-9.09 (m, 1H),8.60 (s, 1H), 8.57 (s, 1H), 7.82 (d, 1H), 7.80 (s, 1H), 7.51 (d, 2H),7.19-7.32 (m, 6H), 7.04 (d, 2H), 6.62-6.64 (m, 2H), 6.39 (s, 1H), 6.08(s, 1H), 3.82 (m, 2H), 3.01 (s, 4H), 2.77 (s, 2H), 2.12-2.16 (m, 6H),1.81 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 2502-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamideEXAMPLE 250A4-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)methanol for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.

EXAMPLE 250B2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 34C for EXAMPLE1F and EXAMPLE 250A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 9.11 (s, 1H), 8.44 (d, 1H), 7.72 (dd, 1H), 7.50(d, 1H), 7.36 (d, 2H), 7.17-7.20 (m, 2H), 7.07 (d, 2H), 6.95 (dd, 2H),6.78 (dd, 1H), 6.72 (dd, 1H), 6.69 (t, 1H), 6.48 (d, 1H), 5.24 (t, 1H),3.54-3.65 (m, 6H), 3.42 (d, 2H), 3.21 (s, 4H), 2.84 (s, 2H), 2.26-2.34(m, 4H), 2.17-2.19 (m, 2H), 1.48-1.55 (m, 4H), 0.95 (s, 6H).

EXAMPLE 2514-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide

The title compound was prepared by substituting tetrahydro2H-pyran-4-amine for 2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol EXAMPLE240B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.21 (s, 1H), 8.58 (d,1H), 8.24 (d, 1H), 7.84 (dd, 1H), 7.52 (d, 1H), 7.38 (dd, 1H), 7.33 (m,3H), 7.29 (d, 1H), 7.23 (d, 1H), 7.03 (d, 2H), 6.64 (dd, 1H), 6.40 (s,1H), 6.08 (s, 1H), 3.90 (m, 3H), 3.47 (m, 2H), 3.03 (br m, 4H), 2.73 (s,2H), 2.19 (br m, 6H), 1.95 (s, 2H), 1.91 (br m, 2H), 1.60 (m, 2H), 1.38(t, 2H), 0.92 (s, 6H).

EXAMPLE 2524-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamideEXAMPLE 252A 4-(morpholinoamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting morpholin-4-amine for4-(1-isopropylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide in EXAMPLE41A.

EXAMPLE 252B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 252A for EXAMPLE 1G is EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) δ 12.38 (s, 1H), 9.26-9.30 (m, 2H), 8.48 (dd, 1H), 8.14 (d,1H), 7.71 (d, 1H), 7.51 (t, 1H), 7.46-7.50 (m, 2H), 7.41-7.45 (m, 3H),7.04 (d, 2H), 6.71 (dd, 1H), 6.54-6.58 (m, 2H), 3.86 (s, 2H), 3.71 (s,2H), 3.01-3.07 (m, 4H), 2.89 (d, 4H), 2.74 (s, 2H), 2.23 (t, 2H),2.07-2.13 (m, 4H), 1.96 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 2532-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE1F and EXAMPLE 252A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) δ 9.26 (s, 1H), 9.13 (d, 1H), 8.31 (dd, 1H), 8.09 (d, 1H),7.67 (d, 1H), 7.46 (d, 2H), 7.10-7.16 (m, 3H), 7.08 (t, 1H), 7.02 (d,1H), 6.93 (dd, 1H), 6.82 (dd, 1H), 6.69 (d, 1H), 3.88 (s, 2H), 3.77 (s,2H), 3.27 (s, 2H), 3.13-3.19 (m, 4H), 2.93 (s, 4H), 2.84 (s, 2H), 2.31(t, 2H), 2.23-2.28 (m, 4H), 2.00 (s, 2H), 1.42 (t, 2H), 0.97 (s, 6H).

EXAMPLE 2542-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamideEXAMPLE 254A3-Nitro-4-[3-(3-oxo-piperazin-1-yl)-propylamino]-benzenesulfonamide

The title compound was prepared by substituting4-(3-aminopropyl)-piperazine-2-one for tert-butyl4-aminopiperidine-1-carboxylate in EXAMPLE 140A.

EXAMPLE 254B2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared by susbtituting EXAMPLE 5B for EXAMPLE1F and EXAMPLE 254A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.85 (t, 1H), 8.47 (d, 1H), 7.80-7.72 (m, 2H),7.51 (d, 1H), 7.41 (dd, 1H), 7.36 (d, 2H), 7.18-7.03 (m, 4H), 7.00 (td,1H), 6.75 (dd, 1H), 6.71 (d, 1H), 6.30 (d, 1H), 3.46 (q, 2H), 3.22-3.11(m, 6H), 2.97 (s, 2H), 2.79 (br s, 2H), 2.59 (t, 2H), 2.47 (t, 2H),2.31-2.12 (m, 6H), 1.97 (br s, 2H), 1.82 (m, 2H), 1.46 9t, 2H), 0.94 (s,6H).

EXAMPLE 2552-(6-aminopyridin-3-yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamideEXAMPLE 255A methyl 2-(6-aminopyridin-3-yloxy)-4-fluorobenzoate

A mixture of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.039g), CsF (1.956 g), bis(triphenylphosphine)palladium(II)dichloride (0.301g), and methyl 2-bromo-4-fluorobenzoate (1.0 g) in 50 mLdimethoxyethane-methanol (1:1) was heated at 80° C. for 2.5 hours. Thereaction mixture was partitioned between water and ethyl acetate. Theorganic phase was washed with brine, dried over MgSO₄, filtered, adconcentrated. The residue was chromatographed on silica gel with 25-80%ethyl acetate in hexanes.

EXAMPLE 255B methyl2-(6-aminopyridin-3-yloxy)-4-(4-((2-(4-chlorphenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 255A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 255C methyl2-(6-butyoxycarbonylamino)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 255B for EXAMPLE219B in EXAMPLE 219C.

EXAMPLE 255D2-(6-(tert-butoxycarbonylamino)pyridin-3-yloxy))-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 255C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 255E tert-butyl5-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-nitro-4(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)phenylsulfonylcarbamoyl)phenoxy)pyridin-2-ylcarbamate

The title compound was prepared by substituting EXAMPLE 255D for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G respectivelyln EXAMPLE 1H.

EXAMPLE 255F2-(6-aminopyridin-3-yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 255E for EXAMPLE1A in EXAMPLE 1B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 0.96 (s, 6H)1.42 (t, 2H) 1.61-1.75 (m, 2H) 1.92-2.05 (m, 6H) 2.21 (s, 5H) 2.28-2.42(m, 3H) 2.80-3.57 (m, 14H) 3.95-4.00 (m, 2H) 6.31 (d, 1H) 6.68 (d, 1H)6.82 (dd, 1H) 7.08 (d, 2H) 7.15 (s, 1H) 7.28-7.41 (m, 4H) 7.68 (d, 1H)7.85 (dd, 1H) 8.22 (s, 1H) 8.50 (d, 1H).

EXAMPLE 2564-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 256A methyl4-(4-(1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethyl)piperazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxyl)benzoate

The title compound was prepared as described EXAMPLE 110D by replacingEXAMPLE 34A with EXAMPLE 154B.

EXAMPLE 256B4-(4-(1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethyl)piperazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxyl)benzoicacid

The title compound was prepared as described in EXAMPLE 110E byreplacing EXAMPLE 110D with EXAMPLE 256A.

EXAMPLE 256C4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 110F byreplacing EXAMPLE 110E with EXAMPLE 256B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.29 (s, 1H), 11.22 (s, 1H), 8.60 (s, 1H), 8.57(s, 1H), 7.86 (d, 1H), 7.52 (d, 1H), 7.27-7.40 (m, 5H), 7.15 (d, 1H),7.02 (d, 2H), 6.60-6.68 (m, 1H), 6.40 (s, 1H), 6.08 (d, 1H), 3.84 (dd,2H), 3.20-3.32 (m, 4H), 3.01 (s, 4H), 2.59-2.72 (m, 1H), 2.16-2.31 (m,4H), 1.75-2.12 (m, 5H), 1.58-1.65 (m, 2H), 1.31-1.41 (m, 2H), 1.20-1.29(m, 2H), 1.01 (d, 3H), 0.91 (s, 3H), 0.90 (s, 3H).

EXAMPLE 2574-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 209G for EXAMPLE1F and EXAMPLE 254A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.23 (br s, 1H), 8.75 (t, 1H), 8.43 (d, 1H),7.74 (br s, 1H), 7.61 (dd, 1H), 7.51 (d, 1H), 7.35(d, 2H), 7.24 (t, 1H),7.05 (d, 2H), 6.95 (d, 1H), 6.85 (dd, 1H), 6.76 (dd, 1H), 6.42 (d, 1H),6.26 (t, 1H), 6.06 (dd, 1H), 3.43 (q, 2H), 3.20-3.08 (m, 6H), 2.97 (brs, 2H), 2.76 (br s, 2H), 2.57 9t, 2H), 2.47 (t, 2H), 2.27-2.12 (m, 6H),1.97 (br s, 2H), 1.80 (m, 2H), 1.40 (t, 2H), 0.93 (s, 6H).

EXAMPLE 2584-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamideEXAMPLE 258A

The title compound was prepared by substituting(tetrahydro-2H-pyran-3-yl)methanamine for1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.

EXAMPLE 258B(S)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide

The racemic mixture of EXAMPLE 258A was resolved by chiral SFC on an ADcolumn (21 mm i.d.×250 mm in length) using a gradient of 10-30% 0.1%diethylamine methanol in CO₂ over 15 minutes (oven temperature: 40° C.;flow rate: 40 mL/minute) to provide the title compound.

EXAMPLE 258C(R)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylzmino)benzenesulfonamide

The racemic mixture of EXAMPLE 258A was resolved by chiral SFC on an ADcolumn (21 mm i.d.×250 mm in length) using a gradient of 10-30% 0.1%diethylamine methanol in CO₂ over 15 minutes (oven temperature: 40° C.;flow rate: 40 mL/minute) to provide the title compound.

EXAMPLE 258D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared as described in EXAMPLE 110F byreplacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 154E and EXAMPLE258B, respectively. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.22 (s,2H), 8.50-8.65 (m, 2H), 7.86 (dd, 1H), 7.51 (d, 1H), 7.38 (t, 1H),7.28-7.35 (m, 4H), 7.13 (d, 1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.41 (s,1H), 6.09 (d, 1H), 3.79 (dd, 1H), 3.68-3.74 (m, 1H), 3.14-3.32 (m, 4H),3.03 (s, 4H), 2.73 (s, 2H), 2.08-2.25 (m, 6H), 1.78-1.97 (m, 4H),1.55-1.66 (m, 1H), 1.41-1.52 (m, 1H), 1.23-1.40 (m, 3H), 0.92 (s, 6H).

EXAMPLE 2594-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared as described in EXAMPLE 110F byreplacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 154E and EXAMPLE258C, respectively. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.22 (s,2H), 8.50-8.65 (m, 2H), 7.86 (dd, 1H), 7.51 (d, 1H), 7.38 (t, 1H),7.28-7.35 (m, 4H), 7.13 (d, 1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.41 (s,1H), 6.09 (d, 1H), 3.79 (dd, 1H), 3.68-3.74 (m, 1H), 3.14-3.32 (m, 4H),3.03 (s, 4H), 2.73 (s, 2H), 2.08-2.25 (m, 6H), 1.78-1.97 (m, 4H),1.55-1.66 (m, 1H), 1.41-1.52 (m, 1H), 1.23-1.40 (m, 3H), 0.92 (s, 6H).

EXAMPLE 260 tert-butyl5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate EXAMPLE 260A tert-butyl5-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of 1,2,3,4-tetrahydroisoquinolin-5-ol, hydrochloric acid (1.0g), di-tert-butyl dicarbonate (1.27 g) and 1.0 N aqueous NaOH (14.5 mL)in dioxane (20 mL) was stirred at room temperature for 16 hours. Thereaction mixture was partitioned between water and ethyl acetate. Theaqueous layer was neutralized with 5% aqueous HCl. The combined organiclayers were washed with brine, dried (MgSO₄), filtered, andconcentrated. The residue was purified by flash chromatography on silicagel to give the title compound.

EXAMPLE 260B tert-butyl5-(2-(ethoxycarbonyl)-5-fluorophenoxy)-3,4-(dihydroisoquinoline-2(1H)-carboxylate

The title compound was prepared by ssubstituting EXAMPLE 260A for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 260C tert-butyl5-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(ethoxycarbonyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-carboxylate

The title compound was prepared by substituting EXAMPLE 260B for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 260D2-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 260C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 260E2-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonicanhydride

The title compound was prepared by substituting EXAMPLE 260D for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 8.63 (s, 1H),8.45 (s, 1H), 7.70 (d, 1H), 7.50 (d, 1H), 7.35 (d, 1H), 7.15 (d, 1H),7.06 (d, 2H), 6.97 (t, 1H), 6.80 (d, 1H), 6.73 (dd, 1H), 6.37 (d, 1H),6.31 (d, 1H), 4.48 (s, 2H), 3.86 (dd, 2H), 3.53 (t, 2H), 3.14 (s, 4H),2.67-2.75 (m, 2H), 2.16-2.30 (m, 6H), 1.63 (d, 2H), 1.43 (s, 9H), 0.94(s, 6H).

EXAMPLE 2612-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamideEXAMPLE 261A 4-Fluoro-2-(6-nitro-pyridin-3-yloxy)-benzoic acid methylester

Methyl 4-fluoro-2-hydroxybenzoate (3.00 g), 5-chloro 2-nitropyridine(3.08 g), and potassium carbonate (4.87 g) were added todimethylsulfoxide (50 mL), heated to 110° C. for one hour, cooled, addedto water, and extracted with ethyl ether. The ether was washed withbrine and dried on anhydrous sodium sulfate. The solution was filteredand concentrated and purified by flash column chromatography on silicagel using 10% ethyl acetate in hexanes increasing to 20% ethyl acetatein hexanes and increasing again to 30% ethyl acetate in hexanes.

EXAMPLE 261B 2-(6-Amino-pyridin-3-yloxy)-4-fluoro-benzoic acid methylester

EXAMPLE 261A (1015 mg), cyclohexene (3.52 mL, 2853 mg), and 10%palladium on carbon (100 mg) were added to ethanol (12 mL)and ethylacetate (4 mL) and heated at 75° C. for three hours. The solution wascooled and vacuum filtered over diatomaceous earth. The solvent wasremoved under vacuum.

EXAMPLE 261C2-(6-Amino-pyridin-3-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoicacid methyl ester

The title compound was prepared by substituting EXAMPLE 261B for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 261D2-(6-Amino-pyridin-3-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoicacid

The title compound was prepared by substituting EXAMPLE 261C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 261E2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 261D for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.53 (br s, 1H), 8.19 (br s, 1H), 7.85 (dd, 1H),7.66 (br s, 1H), 7.47 (d, 1H), 7.36 (d, 2H), 7.25-7.14 (m, 1H), 7.10 (m,1H), 7.07 (d, 2H), 6.58 (dd, 1H), 6.43 (d, 1H), 6.10 (br s, 1H), 5.81(m, 2H), 3.94 (d, 2H), 3.03 (br s, 6H), 2.73 (m, 2H), 2.24-2.12 (m, 8H),2.09-2.00 (m, 2H), 1.97 (br s, 2H), 2.09-2.00 (m, 2H), 1.84-1.74 (m,2H), 1.70-1.60 (m, 2H), 1.58-1.47 (m, 4H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 2624-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 262A methyl5,5-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

The title compound was prepared by substituting4,4-dimethyl-2-methoxycarbonylcyclohexanone for5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 3B.

EXAMPLE 262B methyl2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarboxylate

The title compound was prepared by substituting EXAMPLE 262A for EXAMPLE3B in EXAMPLE 3C.

EXAMPLE 262C (2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methanol

The title compound was prepared by substituting EXAMPLE 262B for EXAMPLE3C in EXAMPLE 3D.

EXAMPLE 262D 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde

The title compound was prepared as described in EXAMPLE 53F by replacingEXAMPLE 53E with EXAMPLE 262C.

EXAMPLE 262E tert-butyl4-((2-(4-chlorphenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

The title compound was prepared as described in EXAMPLE 1A by replacing4′-chlorobiphenyl-2-carboxaldehyde with EXAMPLE 262D.

EXAMPLE 262F1-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazine

The title compound was prepared as described in EXAMPLE 110C byreplacing EXAMPLE 110B with EXAMPLE 262E.

EXAMPLE 262G methyl4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl0methyl)piperazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoate

The title compound was prepared as described in EXAMPLE 110D byreplacing EXAMPLE 34A and EXAMPLE 110C with EXAMPLE 154B and EXAMPLE262F, respectively.

EXAMPLE 262H4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoicacid

The title compound was prepared as described in EXAMPLE 110E byreplacing EXAMPLE 110D with EXAMPLE 262G.

EXAMPLE 262I4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 110F byreplacing EXAMPLE 110E with EXAMPLE 262H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.27 (s, 1H), 11.22 (s, 1H), 8.61 (t, 1H), 8.58(d, 1H), 7.86 (dd, 1H), 7.51 (d, 1H), 7.38 (t, 1H), 7.31-7.36 (m, 3H),7.30 (d, 1H), 7.16 (d, 1H), 7.07 (d, 2H), 6.65 (dd, 1H), 6.41 (s, 1H),6.08 (d, 1H), 3.84 (dd, 2H), 3.22-3.32 (m, 4H), 3.02 (s, 4H), 2.68 (s,2H), 2.17 (s, 6H), 1.84 -1.96 (m, 3H), 1.57-1.65 (m, 2H), 1.39 (t, 2H),1.20-1.31 (m, 2H), 0.92 (s, 6H).

EXAMPLE 2634-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 263A 4-(2-methoxyethylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting 2-methoxyethanamine for3-(N-morpholinyl)-1-propylamine in EXAMPLE 4A.

EXAMPLE 263B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 263A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (4600 MHz,dimethylsulfoxide-d₆) δ 11.28 (s, 1H), 11.21 (s, 1H), 8.58 (m, 2H), 7.87(dd, 1H), 7.50 (d, 1H), 7.32 (m, 5H), 7.15 (d, 1H), 7.03 (d, 2H), 6.65(dd, 1H), 6.40 (m, 1H), 6.10 (m, 1H), 3.58 (m, 4H), 3.30 (s, 3H), 3.04(m, 4H), 2.73 (s, 2H), 2.17 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92(s, 6H).

EXAMPLE 2644-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyloxy)phenyl]sulfonyl}benzamideEXAMPLE 264A3-nitro-4((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

Tetrahydro-2H-pyran-4-yl)methanol (2.0 g) in tetrahydrofuran (20 mL) wastreated with 60% NaH (1.377 g). The solution was stirred for 20 minutesat room temperature. To this solution was added4-fluoro-3-nitrobenzenesulfonamide (2.84 g) portion-wise. The reactionwas stirred for another 2 hours. The mixture was poured into water,neutralized with 10% HCl, and extracted with ethyl acetate three times.The combined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified with flash columnchromatography on silica gel eluting with 20%-60% ethyl acetate inhexanes.

EXAMPLE 264B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyloxy)phenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 264A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.12 (s, 1H), 8.10 (d, 1H), 7.52 (d, 1H), 7.45(d, 1H), 7.38 (d, 1H), 7.33-7.35 (m, 3H), 7.28 (d, 1H), 7.04 (d, 2H),6.65 (dd, 1H), 6.41 (s, 1H), 6.10 (s, 1H), 4.09 (d, 2H), 3.88 (dd, 2H),3.05 (s, 4H), 2.80 (br s, 2H), 2.03-2.20 (m, 6H), 1.63-1.65 (m, 2H),1.33-1.40 (m, 4H), 0.92 (s, 6H).

EXAMPLE 2652-[(3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 265A ethyl 2-(1H-indol-5-yloxy)-4-fluorobenzoate

The title compound was prepared by substituting 5-indolol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 265B ethyl 2-(3-chloro-1H-indol-5-yloxy)-4-fluorobenzoate

V-Chloro-succinimide (160 mg) was added portionwise to a solution ofEXAMPLE 265A (300 mg) in toluene (10 mL) and the mixture was stirred atroom temperature for about two hours. The mixture was chromatographed ona silica gel column with 30% ethyl acetate in hexane to give the titlecompound.

EXAMPLE 265C ethyl2-(3-chloro-1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 265B for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 265D2-(3-chloro-1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 265C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 265E2-(3-chloro-1H-indol-5-yloxy-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 265D for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.42 (s,1H), 11.30 (br s, 1H), 8.60 (t, 1H), 8.54 (d, 1H), 7.78 (dd, 1H), 7.55(d, 1H), 7.50 (d, 1H), 7.42 (d, 1H), 7.34 (d, 2H), 7.09 (d, 1H), 7.04(d, 2H), 7.00 (d, 1H), 6.92 (dd, 1H), 6.68 (dd, 1H), 6.16 (d, 1H), 3.85(dd, 2H), 3.28 (dd, 2H), 3.07 (m, 4H), 2.75 (m, 2H), 2.25-2.15 (m, 6H),1.95 (br. s, 2H), 1.90 (m, 1H), 1.61 (dd, 2H), 1.38 (t, 2H), 1.27 (m,2H), 0.92 (s, 6H).

EXAMPLE 2662-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 266A ethyl 2-(1H-indol-4-yloxy)-4-fluorobenzoate

The title compound was prepared by substituting 4-indolol for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 266B ethyl 2-(3-chloro-1H-indol-4-yloxy)-4-fluorobenzoate

The title compound was prepared by substituting EXAMPLE 266A for EXAMPLE265A in EXAMPLE 265B.

EXAMPLE 266C ethyl2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 266B for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 266D2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 266C for EXAMPLE1E in EXAMPLE 1P.

EXAMPLE 266E2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenyl)sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.56 (s,1H), 11.00 (br s, 1H), 8.64 (t, 1H), 8.54 (d, 1H), 7.81 (dd, 1H), 7.58(d, 1H), 7.45 (d, 1H), 7.34 (d, 2H), 7.26 (d, 1H), 7.16 (d, 2H), 7.10(t, 1H), 7.03 (d, 2H), 6.68 (dd, 1H), 6.62 (d, 1H), 6.10 (d, 1H), 3.85(dd, 2H), 3.26 (t, 2H), 3.02 (br.s, 4H), 2.73 (br.s, 2H), 2.20-2.10 (m,6H), 1.95 (br.s, 2H), 1.90 (m, 1H), 1.61 (dd, 2H), 1.38 (t, 2H), 1.27(m, 2H), 0.92 (s, 6H).

EXAMPLE 2674-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]benzamide

A solution of EXAMPLE 265E (38 mg) in ethanol (5 mL) and 1 N aqueous HCl(5 mL) was stirred at 85° C. for 7 hours. The mixture was cooled toambient temperture and concentrated. The residue was purified onreverse-phase HPLC on a C18 column using a water-acetonitrile gradientwith ammonium acetate buffer to give the title compound. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ 11.30 (br s, 1H), 10.33 (s, 1H), 8.61 (t,1H), 8.54 (d, 1H), 7.84 (dd, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.18 (d,1H), 7.06 (d, 2H), 6.84 (s, 1H), 6.80 (d, 1H), 6.74 (d, 1H), 6.67 (dd,1H), 6.20 (d, 1H), 3.85 (dd, 2H), 3.43 (s, 2H), 3.27 (t, 2H), 3.10(br.s, 4H), 2.77 (br.s, 2H), 2.25-2.10 (m, 6H), 1.97 (br.s, 2H), 1.90(m, 1H), 1.62 (dd, 2H), 1.40 (t, 2H), 1.27 (m, 2H), 0.94 (s, 6H).

EXAMPLE 2684-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 266E for EXAMPLE265E in EXAMPLE 267. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.50 (brs, 1H), 10.40 (s, 1H), 8.59 (t, 1H), 8.54 (d, 1H), 7.72 (d, 1H), 7.47(d, 1H), 7.35 (d, 2H), 7.12 (d, 1H), 7.06 (d, 2H), 6.96 (t, 1H), 6.75(dd, 1H), 6.46 (d, 1H), 6.44 (d, 1H), 6.13 (d, 1H), 3.86 (dd, 2H), 3.28(t, 2H), 3.25 (s, 2H), 3.19 (br.s, 4H), 2.82 (br.s, 2H), 2.28 (br.s,4H), 2.18 (m, 2H), 1.98 (br.s, 2H), 1.90 (m, 1H), 1.63 (d, 2H), 1.41 (t,2H), 1.27 (m, 2H), 0.94 (s, 6H).

EXAMPLE 2694-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 209G for EXAMPLE1F and EXAMPLE 263A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.22 (br s, 1H), 8.55 (t, 1H), 8.43 (d, 1H),7.61 (dd, 1H), 7.51 (d, 1H), 7.35 (d, 2H), 7.24 (t, 1H), 7.05 (d, 2H),7.00 (d, 1H), 6.89 (dd, 1H), 6.77 (dd, 1H), 6.43 (d, 1H), 6.26 (t, 1H),6.06 (t, 1H), 3.63-3.51 (m, 4H), 3.32 (s, 3H), 3.13 (br s, 4H), 2.78 (brs, 2H), 2.31-2.12 (m, 6H), 1.97 (br s, 2H), 1.40 (t, 2H), 0.93 (s, 6H).

EXAMPLE 270 tert-butyl5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamateEXAMPLE 270A methyl2-(6-(bis(tert-butoxycarbonyl)amino)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

EXAMPLE 261C (1080 mg) was dissolved in acetonitrile (12 mL) and4-dimethylaminopyridine (47 mg) and di-tert-butyl dicarbonate (462 mg)were added. The solution was mixed at room temperature for 16 hours, thevolume of solvent reduced, and the material purified by flash columnchromatography on silica gel using 30% ethyl acetate in hexanes.

EXAMPLE 270B2-(6-tert-Butoxycarbonylamino-pyridin-3-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazia-1-yl}-benzoicacid

The title compound was prepared by substituting EXAMPLE 270A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 270C tert-butyl5-(5-(4-{[2-(4-chlorophenyl)-4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate

The title compound was prepared by substituting EXAMPLE 270B for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 9.72 (s, 1H),8.61 (t, 1H), 8.55 (d, 1H), 7.95 (d, 1H), 7.82 (dd, 1H), 7.74 (d, 1H),7.47 (d, 1H), 7.36 (d, 2H), 7.32 (dd, 1H), 7.19 (d, 1H), 7.06 (d, 2H),6.70 (dd, 1H), 6.27 (d, 1H), 3.86 (dd, 2H), 3.13 (br s, 4H), 2.78 (br s,2H), 2.54 (m, 1H), 2.45 (m, 1H), 2.29-2.13 (m, 6H), 1.97 (br s, 2H),1.91 (m, 1H), 1.63 (d, 2H), 1.48 (s, 9H), 1.40 (t, 2H), 1.34-1.20 (m,4H), 0.94 (s, 6H).

EXAMPLE 271 tert-butyl4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamateEXAMPLE 271A 2-(2-Amino-pyridin-4-yloxy)-4-fluoro-benzoic acid methylester

The title compound was prepared by substituting methyl2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and2-aminopyridin-4-ol for 2-methyl-5-indolol in EXAMPLE 3A, except hereheating was at 130° C.

EXAMPLE 271B2-(2-Amino-pyridin-4-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoicacid methyl ester

The title compound was prepared by substituting EXAMPLE 271A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 271C methyl2-(2-(bis(tert-butoxycarbonyl)amino)pyridin-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 271B for EXAMPLE261C in EXAMPLE 270A.

EXAMPLE 271D2-(2-tert-Butoxycarbonylamin-pyridin-4-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoicacid

The title compound was prepared by substituting EXAMPLE 271C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 271E tert-butyl4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate

The title compound was prepared by substituting EXAMPLE 271D for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 9.33 (br s, 1H ), 8.42 (m, 1H), 8.21 (d, 1H),8.02 (m, 1H), 7.76 (m, 1H), 7.58 (d, 1H), 7.40-7.34 (m, 2H), 7.26 (m,1H), 7.20-6.95 (m, 4H), 6.67 (d, 1H), 6.30 (br s, 1H), 3.99-3.90 (m,3H), 3.89 (m, 1H), 3.07 (br s, 4H), 2.76 (br s, 2H), 2.42-2.32 (m, 1H),2.30-2.14 (m, 8H), 2.13-2.03 (m, 2H), 20.2-1.95 (m, 3H), 1.90-1.65 (m,6H), 1.60-1.49 (m, 2H), 1.40 (t, 2H), 1.31 (t, 9H), 0.94 (s, 6H).

EXAMPLE 2722-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 270C for EXAMPLE1A in EXAMPLE 1B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.64 (t, 1H),8.60 (d, 1H), 7.89 (dd, 1H), 7.73 (d, 1H), 7.46 (d, 1H), 7.36 (d, 2H),7.24 (d, 1H), 7.18 (dd, 1H), 7.06 (d, 2H), 6.61 (dd, 1H), 6.47 (d, 1H),6.07 (d, 1H), 5.90 (br s, 2H), 3.85 (dd, 2H), 3.07 (br s, 4H), 2.75 (brs, 2H), 2.28-2.11 (m, 10H), 1.97 (br s, 2H), 1.92 (m, 1H), 1.63 (dd,2H), 1.40 (t, 2H), 1.26 (m, 2H), 0.94 (s, 6H).

EXAMPLE 2732-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 271E for EXAMPLE1A is EXAMPLE 1B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.49 (br s,1H), 8.16-8.06 (m, 1H), 7.86 (dd, 1H), 7.70 (dd, 1H), 7.44 (d, 1H),7.40-7.35 (m, 2H), 7.16-7.09 (m, 2H), 7.07 (d, 2H), 6.59 (d, 1H), 6.45(dd, 1H), 6.19 (d, 1H), 3.96-3.89 (m, 3H), 3.81 (m, 1H), 3.00 (br s,4H), 2.93-2.77 (ro, 2H), 2.74 (br s, 2H), 2.29-2.11 (m, 8H), 2.09-1.95(m, 4H), 1.90-1.46 (m, 8H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 2742-[(5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 274A methyl 2-(5-bromopyridin-3-yloxy)-4-fluorobenzoate

To a solution of 5-bromopyridin-3-ol (1.060 g) in2-methyltetrahydrofuran (15 mL) was added potassium tert-butoxide (6.09mL, 1.0M in tetrahydrofuran) dropwise. After stirring for 5 minutes,methyl 2,4-difluorobenzoate (1.049 g) was added as a solution in2-methyltetrahydrofuran (2 mL) and the reaction was heated to 75° C.N,N-Dimethylformamide (2 mL) was added to the reaction and the reactionwas stirred overnight. The reaction was cooled, diluted with ethylacetate (100 mL) and washed with water (50 mL), brine (50 mL), driedover magnesium sulfate, filtered, and concentrated. Silica gelchromatography (SF40-80) eluting with a gradient of 5% to 35% ethylacetate/hexanes gave the product.

EXAMPLE 274B methyl2-(5-bromopyridin-3-yloxy)-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 274A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 274C2-(5-bromopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 274B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 274D2-[(5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 274C for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.99-11.42(m, 1H), 8.62 (s, 1H), 8.42 (d, 1H), 8.17 (d, 1H), 8.10 (d, 1H), 7.71(dd, 1H), 7.54 (d, 1H), 7.37 (d, 2H), 7.19 (t, 1H), 7.09 (t, 3H), 6.81(dd, 1H), 6.59 (d, 1H), 3.87 (dd, 2H), 3.44-3.15 (m, 8H), 2.88 (s, 2H),2.33 (s, 4H), 2.19 (s, 2H), 1.97 (d, 3H), 1.66 (d, 2H), 1.5-1.20 (m,4H), 0.97 (d, 6H).

EXAMPLE 2752-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 275A ethyl2-(6-chloro-1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLE 38F with EXAMPLE 242F.

EXAMPLE 275B2-(6-chloro-1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro)-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 38 H byreplacing EXAMPLE 38G with EXAMPLE 275A.

EXAMPLE 275C2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 275B and EXAMPLE 1G,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.27 (s, 1H),11.19 (m, 1H), 8.62 (t, 1H), 8.58 (d, 1H), 7.84 (dd, 1H), 7.54 (m, 3H),7.43 (m, 1H), 7.36 (m, 3H), 7.14 (m, 3H), 6.66 (dd, 1H), 6.43 (s, 1H),6.00 (d, 1H), 4.10 (s, 2H), 3.85 (dd, 1H), 3.24 (m, 2H), 3.02 (m, 4H),2.85 (m, 2H), 2.16 (m, 6H), 1.90 (m, 1H), 1.62 (m, 2H), 1.28 (m, 4H),1.18 (s, 6H).

EXAMPLE 2762-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F with EXAMPLE 242H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.27 (s, 1H), 11.12 (m, 1H), 8.60 (m, 2H), 7.85 (dd, 1H), 7.54 (m, 2H),7.44 (m, 1H), 7.33 (d, 3H), 7.16 (d, 1H), 7.03 (d, 2H), 6.66 (dd, 1H),6.43 (s, 1H), 6.00 (d, 1H), 3.85 (m, 2H), 3.28 (m, 4H), 3.02 (m, 4H),2.73 (s, 2H), 2.15 (m, 4H), 1.93 (m, 4H), 1.61 (m, 3H), 1.29 (m, 4H),0.92 (s, 6H).

EXAMPLE 2774-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 277A methyl4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoate

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLE 38E with EXAMPLE 154C.

EXAMPLE 277B4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoicacid

The title compound was prepared as described in EXAMPLE 38H by replacingEXAMPLE 38G with EXAMPLE 277A.

EXAMPLE 277C4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F with EXAMPLE 277B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.30 (m, 1H), 11.21 (s, 1H), 8.61 (m, 2H), 7.86 (dd, 1H), 7.51 (d, 1H),7.37 (m, 3H), 7.30 (m, 1H), 7.15 (m, 3H), 6.66 (dd, 1H), 6.41 (m, 1H),6.00 (d, 1H), 4.10 (s, 2H), 3.84 (dd, 2H), 3.28 (m, 4H), 3.03 (m, 4H),2.82 (s, 2H), 2.23 (m, 5H), 1.89 (m, 1H), 1.62 (m, 2H), 1.26 (m, 4H),1.19 (s, 6H).

EXAMPLE 278 tert-butyl5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-3-ylcarbamateEXAMPLE 278A methyl2-(5-(tert-butoxycarbonylamino)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

EXAMPLE 274B (0.135 g) tert-butylcarbamate (0.028 g) and cesiumcarbonate (0.106 g) were mixed together in dioxane (2 mL).Diacetoxypalladium (2.425 mg) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.012 g,)were added and the reaction was degassed with nitrogen then sealed andheated to 85° C. The reaction was stirred for 16 hours, cooled, loadedonto silica gel (40 g) and eluted using a gradient of 0.5% to 7.5%methanol/dichlormethane to yield the product.

EXAMPLE 278B2-(5-(tert-butoxycarbonylamino)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methylpiperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 278A for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 278C tert-butyl5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-3-ylcarbamate

The title compound was prepared by substituting EXAMPLE 278B for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, CDCl₃) δ 9.75 (s, 1H), 8.84 (d, 1H),8.51 (d, 1H), 8.32 (d, 1H), 8.13 (dd, 1H), 8.08 (d, 1H), 7.92 (d, 1H),7.87 (s, 1H), 7.24 (d, 2H), 6.92 (dd, 3H), 6.65 (s, 1H), 6.58 (dd, 1H),6.06 (d, 1H), 4.02 (dd, 2H), 3.42 (dd, 2H), 3.32-3.21 (m, 2H), 3.14 (s,4H), 2.77 (s, 2H), 2.22 (d, 6H), 1.98 (s, 3H), 1.70 (t, 2H), 1.56-1.36(m, 13H), 0.95 (s, 6H).

EXAMPLE 2792-[5-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

To EXAMPLE 278C (0.050 g) in dichloromethane (2 mL) was addedtrifluoroacetic acid (0.061 mL) and the reaction stirred at roomtemperature. After stirring for 19 hours, the reaction was concentratedthen dried under high vacuum. The residue was dissolved indichloromethane (1 mL) and neutralized with N,N-diisopropylethylamine(0.208 mL). The solution was loaded onto silica gel (GraceResolv 12 g)and the product eluted using a gradient of 0.5% methanol/dichloromethaneto 5% methanol/dichloromethane over 30 minutes (Flow=30 mL/min) to givethe title compound. ¹H NMR (300 MHz, CDCl₃) δ 8.82 (d, 1H), 8.50 (s,1H), 8.11 (dd, 1H), 7.98 (d, 1H), 7.91 (d, 1H), 7.82 (d, 1H), 7.30-7.14(m, 2H), 7.01-6.83 (m, 3H), 6.69 (t, 1H), 6.58 (dd, 1H), 6.10 (d, 1H),4.10-3.98 (m, 2H), 3.88 (s, 2H), 3.42 (dd, 2H), 3.34-3.20 (m, 2H), 3.14(d, 4H), 2.78 (s, 2H), 2.22 (d, 6H), 1.99 (s, 3H), 1.73 (d, 2H),1.62-1.10 (m, 4H), 0.95 (s, 6H).

EXAMPLE 280 tert-butyl4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate

The title compound was prepared by substituting EXAMPLE 271D for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 9.33 (br s,1H), 8.65 (t, 1H), 8.55 (br s, 1H), 8.16 (br s, 1H), 7.82 (d, 1H), 7.57(d, 1H), 7.44 (t, 1H), 7.35 (d, 2H), 7.32-7.13 (m, 2H), 7.11 (d, 1H),7.06 (d, 2H), 6.71 (d, 1H), 3.86 (dd, 2H), 3.09 (br s, 4H), 2.73 (d,2H), 2.25-2.12 (m, 8H), 1.97 (br s, 2H), 1.91 (m, 1H), 1.66-1.47 (m,4H), 1.40 (t, 2H), 1.31 (s, 9H), 1.24 (t, 2H), 0.94 (s, 6H).

EXAMPLE 2812-[3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 265D for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H. (¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.34 (s, 1H), 8.48 (d, 1H), 8.15 (d, 1H), 7.74(dd, 1H), 7.53-7.51 (m, 2H), 7.37 (d, 1H), 7.34 (d, 2H), 7.04 (d, 2H),7.00 (d, 1H), 6.87-6.85 (m, 2H), 6.64 (dd, 1H), 6.19 (d, 1H), 3.94 (dd,2H), 3.75 (m, 1H), 3.28 (dd, 2H), 3.02 (m, 6H), 2.72 (m, 2H), 2.62 (m,1H), 2.25-2.10 (m, 6H), 2.00 (m, 2H), 1.95 (br.s, 2H), 1.91 (m, 2H),1.77 (d, 2H), 1.70-1.60 (m, 2H), 1.55-1.45 (m, 2H), 1.38 (m, 2H), 0.92(s, 6H).

EXAMPLE 2822-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pryan-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 280 for EXAMPLE1A in EXAMPLE 1B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.59 (t, 1H),8.54 (d, 1H), 7.84 (dd, 1H), 7.73 (m, 1H), 7.46 (d, 1H), 7.36 (d, 2H),7.16 (d, 1H), 7.14-7.10 (m, 1H), 7.06 (d, 2H), 6.95 (d, 1H), 6.66 (d,2H), 6.46 (m, 1H), 6.15 (d, 1H), 3.86 (dd, 2H), 3.07 (br s, 4H), 2.76(br s, 2H), 2.30-2.12 (m, 6H), 1.97 (br s, 2H), 1.90 (m, 1H), 1.63 (d,2H), 1.40 (t, 2H), 1.35-1.15 (m, 6H), 0.94 (s, 6H).

EXAMPLE 2834-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-hydroxypyridin-3-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2-H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 283A methyl 2-(6-(benzyloxy)pyridin-3-yloxy)-4-fluorobenzoate

To 6-(benzyloxy)pyridin-3-ol (1.10 g) in 2-methyltetrahydrofuran (20 mL)was added potassium t-butoxide (5.47 mL, 1.0M in tetrahydrofuran). Afterstirring for 15 minutes, methyl 2,4-difluorobenzoate (1.035 g) in2-methyltetrahydrofuran (2 mL) was added and the reaction heated to 75°C. for 1 hour. The reaction was cooled, diluted with ethyl acetate (150mL), washed with water (50 mL), brine (50 mL), dried over magnesiumsulfate, filtered and concentrated. Silica gel chromatography (SF40-80g)eluting with a gradient of 5% to 20% ethyl acetate/hexanes gave thetitle compound.

EXAMPLE 283B methyl2-(6-(benzyloxy)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 283A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 283C2-(6-(benzyloxy)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 283B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 283D2-{[6-(benzyloxy)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 283C for EXAMPLE1F in EXAMPLE 1H.

EXAMPLE 283E4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-hydroxypyridin-3-yloxy)-N-(3-nitro-4-((tetrahydro-2-H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

To2-(6-(benzyloxy)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide(0.132 g) in dichloromethane (1 mL) was added trifluoroacetic acid (0.33mL) and the reaction was sealed in a vial under nitrogen and heated to40° C. After stirring for 16 hours, the reaction was cooled, dilutedwith dichloromethane (50 mL) and washed with sodium carbonate (2×25 mL).The organic layer was dried over magnesium sulfate, filtered, andconcentrated. Silica gel chromatography (GraceResolv 12 g) eluting witha gradient of 0.3% to 3% methanol/dichloromethane (Flow=36 mL/minute)over 30 minutes gave the title compound. ¹H NMR (300 MHz, CDCl₃) δ12.51-11.38 (m, 1H), 9.78 (s, 1H), 8.89 (d, 1H), 8.52 (t, 1H), 8.19 (dd,1H), 7.92 (d, 1H), 7.43-7.33 (m, 2H), 7.24 (d, 2H), 7.00-6.89 (m, 3H),6.74-6.67 (m, 1H), 6.35 (dd, 1H), 6.00 (d, 1H), 4.00 (d, 2H), 3.42 (dd,2H), 3.34-3.23 (m, 2H), 3.16 (s, 4H), 2.79 (s, 2H), 2.24 (d, 6H), 1.99(s, 3H), 1.72 (s, 2H), 1.55-1.33 (m, 4H), 0.96 (s, 6H).

EXAMPLE 2842-{[6-(benzyloxy)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pryan-4ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 283D. ¹H NMR(300 MHz, CDCl₃) δ 9.93 (s, 1H), 8.88 (d, 1H), 8.52 (t, 1H), 8.17 (dd,1H), 8.05 (d, 1H), 7.92 (d, 1H), 7.49 (d, 2H), 7.45-7.34 (m, 4H), 7.24(d, 2H), 6.97-6.85 (m, 4H), 6.54 (dd, 1H), 5.95 (d, 1H), 5.41 (s, 2H),4.02 (dd, 2H), 3.48-3.35 (m, 2H), 3.30-3.23 (m, 2H), 3.15-3.02 (m, 4H),2.77 (s, 2H), 2.23 (dd, 6H), 1.95 (d, 3H), 1.71 (s, 2H), 1.59-1.33 (m,4H), 1.03-0.89 (m, 6H).

EXAMPLE 2854-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 285A 4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide

(1,4-Dioxan-2-yl)methanol (380 mg) in tetrahydrofuran (30 mL) wastreated with sodium hydride (60%, 245 mg) at room temperature for 30minutes. The reaction mixture was cooled in an ice bath and4-fluoro-3-nitrobenzenesulfonamide (675 mg) was added. The resultingmixture was stirred at room temperature for 2 hours and another portionof sodium hydride (60%, 245 mg) was added. The reaction mixture wasstirred overnight and quenched with ice water (3 mL). The cloudy mixturewas filtered and the filtrate was concentrated. The residue wastriturated with methanol to give the title compound.

EXAMPLE 2854-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared as described in EXAMPLE 110F byreplacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 154E and EXAMPLE285A, respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.21 (s,2H), 8.38 (d, 1H), 8.10 (d, 1H), 7.52 (d, 1H), 7.47 (d, 1H), 7.38 (t,1H), 7.32-7.36 (m, 3H), 7.27 (d, 1H), 7.04 (d, 2H), 6.65 (dd, 1H), 6.40(s, 1H), 6.10 (d, 1H), 4.20-4.29 (m, 2H), 3.85-3.91 (m, 1H), 3.82 (dd,1H), 3.74-3.78 (m, 1H), 3.59-3.69 (m, 2H), 3.40-3.51 (m, 2H), 3.06 (s,4H), 2.82 (s, 2H), 2.26 (s, 4H), 2.14 (s, 2H), 1.95 (s, 2H), 1.39 (t,2H), 0.92 (s, 6H).

EXAMPLE 2862-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.51 (s, 1H), 9.17 (s, 1H), 8.48 (s, 1H), 7.83(d, 1H), 7.58 (d, 2H), 7.43 (s, 1H), 7.33 (d, 2H), 7.20 (d, 1H),7.07-7.03 (m, 3H), 6.66 (d, 1H), 6.52 (m, 1H), 6.10 (s, 1H), 3.00 (m,3H), 2.90 (m, 6H), 2.71 (br.s, 2H), 2.50 (s, 3H), 2.32 (m, 3H), 2.15 (m,6H), 1.95 (br.s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 2874-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 286 for EXAMPLE265E in EXAMPLE 267. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 10.31 (s,1H), 8.86 (s, 1H), 8.29 (s, 1H), 7.54 (m, 2H), 7.42 (d, 1H), 7.36 (d,2H), 7.08 (d, 2H), 6.91 (t, 1H), 6.68 (d, 1H), 6.39 (m, 2H), 6.06 (d,1H), 3.34 (m, 4H), 3.27 (s, 2H), 3.08 (br.s, 4H), 2.86 (m, 4H), 2.76 (s,2H), 2.28 (s, 3H), 2.25-2.10 (m, 6H), 1.97 ((br.s, 2H), 1.40 (t, 2H),0.94 (s, 6H).

EXAMPLE 2884-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamideEXAMPLE 288A2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE1F and EXAMPLE 3I for EXAMPLE 1G is EXAMPLE 1H.

EXAMPLE 288B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 288A for EXAMPLE265E in EXAMPLE 267. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 10.29 (s,1H), 8.34 (s, 1H), 8.05 (br. d, 1H), 7.64 (d, 1H), 7.54 (d, 1H), 7.36(d, 2H), 7.07 (d, 2H), 7.01 (d, 1H), 6.91 (t, 1H), 6.68 (d, 1H), 6.38(m, 2H), 6.08 (d, 1H), 3.80 (br. s, 1H), 3.34 (m, 2H), 3.23 (s, 2H),3.09 (br.s, 4H), 2.84 (m, 2H), 2.76 (s, 2H), 2.62 (br.s, 2H), 2.24 (s,3H), 2.25-2.05 (m, 6H), 1.98 ((br.s, 2H), 1.76 (m, 2H), 1.40 (t, 2H),0.94 (s, 6H).

EXAMPLE 2894-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamideEXAMPLE 289A2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1B.

EXAMPLE 289B4-(4-((2-(4-chloropbenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)phenylsulfonyl-2-(2-oxoindolin-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 289A for EXAMPLE265E in EXAMPLE 267. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 10.32 (s,1H), 8.37 (s, 1H), 8.12 (br.s, 1H), 7.68 (d, 1H), 7.52 (d, 1H), 7.36 (d,2H), 7.07 (m, 3H), 6.93 (t, 1H), 6.69 (d, 1H), 6.40 (m, 2H), 6.09 (d,1H), 3.94 (m, 2H), 3.83 (br.s, 1H), 3.34 (m, 7H), 3.23 (s, 2H), 3.12(br.s, 4H), 2.77 (s, 2H), 2.62 (s, 2H), 2.30-2.00 (m, 8H), 1.98 ((br.s,2H), 1.85 (m, 2H), 1.73 (m, 2H), 1.54 (m, 2H), 1.40 (t, 2H), 0.94 (s,6H).

EXAMPLE 2902-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 242H and EXAMPLE 285A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.25 (s, 1H),8.37 (d, 1H), 8.09 (m, 1H), 7.48 (m, 4H), 7.33 (m, 3H), 7.05 (m, 3H),6.65 (dd, 1H), 6.42 (m, 1H), 6.01 (d, 1H), 4.25 (m, 2H), 3.83 (m, 3H),3.63 (m, 3H), 3.45 (m, 2H), 3.04 (m, 4H), 2.74 (m, 2H), 2.24 (m, 5H),1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 2912-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzmideEXAMPLE 291A 4-((1,4-dioxan-2-yl)methylamino-3-nitrobenzenesulfonamide

The title compound was prepared as described in EXAMPLE 4A by replacing3-(N-morpholinyl)-1-propylamine with C-[1,4]dioxan-2-yl-methylamine.

EXAMPLE 291B2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 242H and EXAMPLE 291A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.25 (s, 1H),8.37 (d, 1H), 8.09 (dd, 1H), 7.54 (m, 2H), 7.44 (m, 2H), 7.33 (m, 3H),7.05 (m, 2H), 6.65 (dd, 1H), 6.42 (s, 1H), 6.01 (d, 1H), 3.83 (m, 3H),3.63 (m, 2H), 3.45 (m, 2H), 3.04 (m, 4H), 2.74 (m, 2H), 2.24 (m, 5H),1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 2924-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 154E and EXAMPLE 291A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.20 (s, 1H),8.58 (d, 2H), 7.95 (s, 1H), 7.88 (dd, 1H), 7.51 (d, 1H), 7.34 (m, 5H),7.15 (d, 1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.40 (s, 1H), 3.78 (m, 3H),3.61 (m, 2H), 3.46 (m, 3H), 3.03 (m, 4H), 2.89 (s, 3H), 2.73 (m, 2H),2.15 (m, 4H), 1.95 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 293Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 242H and EXAMPLE 205A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.23 (s, 1H),8.53 (d, 1H), 8.17 (d, 1H), 7.82 (dd, 1H), 7.53 (t, 2H), 7.41 (t, 1H),7.33 (d, 2H), 7.24 (s, 1H), 7.11 (d, 1H), 7.03 (d, 2H), 6.64 (dd, 1H),6.40 (s, 1H), 6.01 (d, 1H), 3.60 (m, 5H), 3.02 (m, 4H), 2.71 (s, 2H),2.57 (m, 6H), 2.03 (m, 12H), 1.39 (m, 6H), 0.92 (s, 6H).

EXAMPLE 294Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 275B and EXAMPLE 205A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.20 (s, 1H),8.50 (d, 1H), 8.14 (d, 1H), 7.79 (dd, 1H), 7.54 (m, 2H), 7.38 (m, 3H),7.12 (m, 4H), 6.63 (dd, 1H), 6.38 (s, 1H), 6.02 (d, 1H), 4.10 (s, 2H),3.59 (m, 6H), 3.31 (m, 4H), 3.01 (m, 4H), 2.81 (s, 2H), 2.68 (s, 2H),2.54 (m, 3H), 2.03 (m, 5H), 1.39 (m, 4H), 1.20 (s, 6H).

EXAMPLE 2954-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 277B and EXAMPLE 205A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H),8.53 (d, 1H), 8.16 (d, 1H), 7.83 (dd, 1H), 7.52 (d, 1H), 7.34 (m, 4H),7.20 (dd, 1H), 7.13 (m, 3H), 6.63 (dd, 1H), 6.38 (s, 1H), 6.09 (d, 1H),4.10 (s, 2H), 4.01 (s, 1H), 3.61 (m, 4H), 3.02 (m, 4H), 2.81 (s, 2H),2.59 (m, 3H), 2.12 (m, 12H), 1.39 (m, 4H), 1.18 (s, 6H).

EXAMPLE 2964-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 296A 1,6-dioxaspiro[2.5]octane-2-carbonitrile

A mixture of dihydro-2H-pyran- 4(3H)-one (10.0 g) and2-chloroacetonitrile (7.5 g) in tert-butanol (10 mL) was treated with1.0 N potassium tert-butoxide (100 mL) drop-wise over 20 minutes. Thereaction mixture was stirred at room temperature for 16 hours. It wasdiluted with water (10 mL) and 10% aqueous HCl (20 mL). The reactionmixture was concentrated to one-third of its original volume, andextracted with diethyl ether four times. The combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentrated.The residue was purified with flash column chromatography on silica geleluting with 20-40% ethyl acetate in hexanes.

EXAMPLE 296B 2-(4-fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile

EXAMPLE 296A (11.5 g) was dissolved in dichloromethane (40 mL) in apolypropylene bottle. The bottle was cooled to 0° C. To this solutionwas added 70% hydrogen fluoride-pyridine (10.3 mL) slowly. The solutionwas allowed to warm to room temperature over 3 hours, and stirred for 24hours. The reaction mixture was diluted with ethyl acetate (200 mL) andpoured into saturated aqueous NaHCO₃. Additional solid NaHCO₃ was usedto neutralize the solution carefully until bubbling ceased. The organiclayer was isolated, and the aqueous layer was extracted with additionalehtyl acetate three times (150 mL each). The combined organic layerswere washed with 1% aqueous HCl, brine, dried (MgSO₄), filtered andconcentrated to give the desired compound which was used directly in thenext reaction.

EXAMPLE 296C (4-fluorotetrahydro-2H-pyran-4-yl)methanol

EXAMPLE 296B (11.8 g) in 2-propanol (150 mL) and water (37 mL) wascooled to 0° C. To this solution was added sodium borohydride (4.2 g).The solution was stirred and allowed to warm to room temperature over 3hours. The reaction was quenched with acetone, and stirred for another 1hour. The clear liquid was separated from the solid by decanting.Additional ethyl acetate was used to wash the solid, and was decanted.The combined organic solutions were concentrated. The residue waspurified with flash column chromatography on silica gel eluting with20-40% ethyl acetate-hexanes.

EXAMPLE 296D4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide

EXAMPLE 296C (2.0 g) in tetrahydrofuran (20 mL) was treated with 60% NaH(1.3 g). The solution was stirred for 20 minutes at the roomtemperature. To this solution was added4-fluoro-3-nitrobenzenesulfonamide (2.8 g) portion-wise. The reactionwas stirred for another 2 hours. The mixture was poured into water,neutralized with 10% aqueous HCl, and extracted with ethyl acetate threetimes. The combined organic layers were washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was purified with flashcolumn chromatography on silica gel eluting with 20%-60% ethyl acetatein hexanes.

EXAMPLE 296E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE122C and EXAMPLE 296D for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.20 (s, 1H), 8.40 (s, 1H), 8.13 (br d, 1H),7.54 (d, 1H), 7.49 (br d, 1H), 7.38 (dd, 1H), 7.33 (d, 3H), 7.28 (br d,1H), 7.04 (d, 2H), 6.64 (d, 1H), 6.40 (s, 1H), 6.09 (s, 1H), 4.38 (d,2H), 3.78 (m, 2H), 3.60 (m, 2H), 3.06 (v br s, 4H), 2.82 (br s, 2H),2.27 (v br s, 4H), 2.15 (br m, 2H), 1.95 (s, 2H), 1.85 (m, 4H), 1.40 (t,2H), 0.92 (s, 6H).

EXAMPLE 2974-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 277B for EXAMPLE122C and EXAMPLE 296D for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.20 (s, 1H), 8.43 (s, 1H), 8.16 (br d, 1H),7.52 (d, 2H), 7.38 (m, 4H), 7.30 (br d, 1H), 7.11 (d, 2H), 6.64 (d, 1H),6.40 (s, 1H), 6.09 (s, 1H), 4.40 (d, 2H), 4.10 (s, 2H), 3.78 (m, 2H),3.60 (m, 2H), 3.07 (v br s, 4H), 2.84 (br s, 2H), 2.24 (v br s, 4H),2.16 (s, 2H), 1.85 (m, 4H), 1.18 (s, 6H).

EXAMPLE 2984-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by susbtituting EXAMPLE 277B for EXAMPLE122C and EXAMPLE 301B for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.20 (s, 1H), 8.83 (d, 1H), 8.60 (s, 1H), 7.54(d, 1H), 7.38 (d, 2H), 7.37 (m, 1H), 7.33 (d, 1H), 7.21 (br d, 1H), 7.13(d, 2H), 6.66 (dd, 1H), 6.38 (s, 1H), 6.12 (s, 1H), 4.30 (d, 2H), 4.10(s, 2H), 3.85 (dd, 2H), 3.33 (m, 2H), 3.07 (v br s, 4H), 2.95 (br s,2H), 2.31 (v br s, 4H), 2.16 (s, 2H), 2.05 (m, 1H), 1.63 (br m, 2H),1.38 (ddd, 2H), 1.18 (s, 6H).

EXAMPLE 2992-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[-(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 299A tert-butyl 2-(5-hydroxy-1H-indol-3-yl)ethylcarbamate

To a suspension of 3-(2-aminoethyl)-1H-indol-5-ol, hydrochloride (5 g)in dichloromethane (100 mL) was added N-ethyl-N-isopropylpropan-2-amine(3.19 g) followed by a solution of di-tert-butyl dicarbonate (5.64 g) indichloromethane (10 mL). The mixture was stirred at ambient temperatureunder nitrogen 18 hours. The resulting solution was washed with brine,dried over sodium sulfate, filtered and concentrated. The crude materialwas purified on silica gel with 1-5% methanol in methylene chloride.

EXAMPLE 299B ethyl2-(3-(2-(tert-butoxycarbonylamino)ethyl)-1H-indol-5-yloxy)-4-fluorobenzoate

The title compound was prepared by substituting EXAMPLE 299A for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 299C ethyl2-(3-(2-(tert-butoxycarbonylamino)ethyl)-1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 299B for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 299D2-(3-(2-(tert-butoxycarbonylamino)ethyl)-1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 299C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 299E tert-butyl2-(5-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)-1H-indol-3-yl)ethylcarbamate

The title compound was prepared by substituting EXAMPLE 299D for EXAMPLE1F in EXAMPLE 1H.

EXAMPLE 299F2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[-(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

A solution of EXAMPLE 299E (146.6 mg) in dichloromethane (10 mL) wascooled in an ice bath and 2,2,2-trifluoroacetic acid (5 mL) was addeddropwise over 5 minutes. The reaction mixture was stirred 15 minutesunder nitrogen, the ice bath was removed and the reaction was allowed tocome to ambient temperature. The reaction was stirred 1.5 hours and thenconcentrated. The crude material was purified by reverse phasechromatography with ammonium acetate buffer in acetonitrile to give thetitle compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 10.86 (d, 1H),8.39 (d, 1H), 8.33 (t, 1H), 8.06 (br s, 1H), 7.71 (dd, 1H), 7.53 (d,1H), 7.34 (d, 2H), 7.26 (d, 1H), 7.19 (d, 1H), 7.05 (m, 3H), 6.89 (d,1H), 6.70 (dd, 1H), 6.52 (dd, 1H), 6.15 (d, 1H), 3.83 (dd, 2H), 3.22 (m,3H), 2.82-3.00 (m, 8H), 2.72 (s, 2H), 2.16 (m, 6H), 1.96 (s, 2H), 1.88(m, 4H), 1.60 (d, 2H), 1.38 (m, 2H), 1.24 (m, 2H), 0.93 (s, 6H).

EXAMPLE 3002-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 300A tert-butyl2-(5-(5-(4-((2-(4-chlorophenyl)-4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(4-(4-methylpiperazin4-ylamino)-3-nitrophenylsulfonylcarbamoyl)phenoxy)-1H-indol-3-yl)ethylcarbamate

The title compound was prepared by substituting EXAMPLE 299D for EXAMPLE1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 300B2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 300A for EXAMPLE299E in EXAMPLE 299F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 10.88 (d,1H), 8.78 (s, 1H), 8.61 (br s, 1H), 8.38 (d, 1H), 7.76 (dd, 1H), 7.52(d, 1H), 7.42 (d, 1H), 7.34 (d, 2H), 7.27 (d, 1H), 7.20 (d, 1H), 7.05(m, 3H), 6.71 (dd, 1H), 6.51 (dd, 1H), 6.14 (dm, 1H), 3.02-2.80 (m,12H), 2.71 (s, 2H), 2.20-2.11 (m, 9H), 1.95 (s, 2H), 1.90 (s, 6H), 1.38(m, 2H), 0.93 (s, 6H).

EXAMPLE 3014-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 301A

(Tetrahydro-2H-pyran-4-yl)methanol (0.65 g) in tetrahydrofuran (20 mL)was treated with 60% sodium hydride (0.895 g). The reaction mixture wasstirred for 10 minutes. To this solution was added EXAMPLE 305A (1.519g). The reaction mixture was stirred overnight. It was poured intowater, neutralized with 10% aqueous HCl, and extracted with ethylacetate three times. The combined organic layers were washed with brine,dried over MgSO₄, filtered, and concentrated. The residue was purifiedwith flash column chromatography on silica gel eluting with 20%-60%ethyl acetate in hexanes to give the title compound.

EXAMPLE 301B

A mixture of EXAMPLE 301A (0.702 g), dicyanozinc (0.129 g), andtetrakis(triphenylphosphine)palladium(0) (0.231 g) inN,N-dimethylformamide (2 mL) was degassed via vacuum/nitrogen cyclethree times. The reaction mixture was heated at 120° C. for 3 hours.After cooling, it was poured into water and extracted with ethyl acetatethree times. The combined organic layers were washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was purified withflash column chromatography on silica gel eluting with 20%-60%tetrakis(triphenylphosphine)palladium(0) in hexanes to give the titlecompound.

EXAMPLE 301C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1E and EXAMPLE 301B for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.14 (s, 1H), 8.75 (s, 1H), 8.51 (s, 1H), 7.55(d, 1H), 7.32-7.34 (m, 3H), 7.28 (d, 1H), 7.12 (d, 1H), 7.04 (d, 2H),6.62 (dd, 1H), 6.33 (s, 1H), 6.11 (s, 1H), 4.28 (d, 2H), 3.86 (dd, 2H),2.92-3.06 (m, 4H), 2.35-2.38 (m, 2H), 1.95-2.15 (m, 5H), 1.61-1.64 (m,2H), 1,34-1.40 (m, 4H), 0.91 (s, 6H).

EXAMPLE 3022-[(6-amino-5-fluoropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 302A methyl2-(6-chloro-5-fluoropyridin-3-yloxy)-4-fluorobenzoate

To a solution of 6-chloro-5-fluoropyridin-3-ol (0.977 g) in2-methyltetrahydrofuran (12 mL) was added potassium2-methylpropan-2-olate (1.0 M) in tetrahydrofuran, 7.28 mL). Afterstirring for 15 minutes at room temperature, methyl 2,4-difluorobenzoate(1.710 g) was added as a solution 2-methyltetrahydrofuran (2 mL)followed by N,N-dimethylformamide (2 mL) then the reaction was heated to75° C. under a nitrogen atmosphere. After stirring overnight thereaction was cooled, diluted with ethyl acetate (100 mL) and washed withwater (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered,and concentrated. Silica gel chromatography (GraceResolv 40 g) elutingwith a gradient 2% to 15% ethyl acetate/hexanes gave the title compound.

EXAMPLE 302B methyl2-(6-(tert-butoxycarbonylamino)-5-fluoropyridin-3-yloxy)-4-fluorobenzoate

Methyl 2-(6-chloro-5-fluoropyridin-3-yloxy)-4-fluorobenzoate (0.875 g),tert-butyl carbamate (0.410 g), cesium carbonate (1.427 g),diacetoxypalladium (0.033 g) and(9.9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphise) (0.169 g) wereadded to dioxane (10 mL). The reaction was degassed with nitrogen thensealed. The reaction was then heated to 85° C. After stirring for 16hours the reaction was cooled, diluted with water (25 mL) and theproduct was extracted into dichloromethane (2×25 mL). The organic layerwas dried over magnesium sulfate, filtered, and concentrated. Silica gelchromatography (GraceResolv 40 g) eluting with a gradient of 5% to 25%ethyl acetate/hexanes gave the title compound.

EXAMPLE 302C methyl2-(6-(tert-butoxycarbonylamino)-5-fluoropyridin-3-yloxy)-4-(piperazin-1-yl)benzoate

Methyl2-(6-(tert-butoxycarbonylamino)-5-fluoropyridin-3-yloxy)-4-fluorobenzoate(0.170 g) and piperazine (0.154 g) were dissolved in dimethylsulfoxide(2 mL) and heated to 85° C. After 1 hour, the reaction was cooled,poured into dichloromethane (75 mL), and washed with water (30 mL). Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated to give the title compound.

EXAMPLE 302D methyl2-(6-(tert-butoxycarbonylamino)-5-fluoropyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 302C fortert-butyl piperazine-1-carboxylate and EXAMPLE 60D for4′-chlorobiphenyl-5-carboxaldehyde in EXAMPLE 1A.

EXAMPLE 302E2-(6-(tert-butoxycarbonylamino)-5-fluoropyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 302D for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 302F tert-butyl5-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)-3-fluoropyridin-2-ylcarbamate

The title compound was prepared by substituting EXAMPLE 302E for EXAMPLE1F in EXAMPLE 1H.

EXAMPLE 302G2-(6-amino-5-fluoropyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

To EXAMPLE 302F (0.115 g) in dichloromethane (2 mL) was added TFA (0.276mL). After stirring for 3 hours the reaction was concentrated, dissolvedin dichloromethane (50 mL) and washed with aqueous saturated NaHCO₃ (30mL), dried over magnesium sulfate, filtered, and concentrated. Silicagel chromatography (GraceResolv 12 g) eluting with a gradient of 0.5% to3% methanol/dichloromethane gave the title compound. ¹H NMR (300 MHz,CDCl₃) δ 9.86 (s, 1H), 8.88 (d, J=2.2, 1H), 8.52 (s, 1H), 8.17 (dd, 1H),7.92 (d, 1H), 7.83 (d, 1H), 7.26 (s, 1H), 7.11 (dd, 1H), 6.93 (dd, 3H),6.54 (dd, 1H), 5.98 (d, 1H), 4.69 (s, 2H), 4.02 (dd, 2H), 3.42 (d, 2H),3.31-3.23 (m, 2H), 3.12 (s, 4H), 2.78 (s, 2H), 2.25 (s, 6H), 1.99 (s,3H), 1.72 (s, 2H), 1.55-1.34 (m, 4H), 0.96 (s, 6H).

EXAMPLE 3034-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 303A 5,6-dichloropyridine-3-sulfonamide

The title compound was prepared by substituting5,6-dichloropyridine-3-sulfonyl chloride for5-bromo-6-chloropyridine-3-sulfonyl chloride is EXAMPLE 305A.

EXAMPLE 303B5-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 303A for EXAMPLE305A and (tetrahydro-2H-pyran-4-yl)methanol for(1,3-dioxan-4-yl)methanol in EXAMPLE 305B.

EXAMPLE 303C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE122C and EXAMPLE 303B for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.20 (s, 1H), 8.57 (d, 1H), 8.23 (s, 1H), 7.54(d, 1H), 7.37 (dd, 1H), 7.35 (m, 3H), 7.26 (br d, 1H), 7.05 (d, 2H),6.64 (dd, 1H), 6.40 (s, 1H), 6.10 (s, 1H), 4.25 (d, 2H), 3.86 (dd, 2H),3.33 (m, 2H), 3.06 (v br s, 4H), 2.86 (br s, 2H), 2.30 (v br s, 4H),2.05 (m, 1H), 2.15 (br m, 2H), 1.95 (s, 2H), 1.63 (br d, 2H), 1.40 (t,2H), 1.33 (ddd, 2H), 0.92 (s, 6H).

EXAMPLE 304Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy]benzamideEXAMPLE 304A4-Fluoro-2-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-benzoic acidmethyl ester

The title compound was prepared by substituting methyl2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and5-hydroxy-3,4-dihydro-2H-isoquinolin-1-one for 2-methyl-5-indolol inEXAMPLE 3A, except here the heating was at 130° C.

EXAMPLE 304B4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-pieprazin-1-yl}-2-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-benzoicacid methyl ester

The title compound was prepared by substituting EXAMPLE 304A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 304C4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmeithyl]-piperazin-1-yl}-2-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-benzoicacid

The title compound was prepared by substituting EXAMPLE 304B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 304DTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 304C for EXAMPLE1F and EXAMPLE 205A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.37 (br s, 1H), 8.22-8.18 (m, 2H), 7.93-7.84(m, 2H), 7.57-7.52 (m, 1H), 7.45 (d, 1H), 7.36 (d, 2H), 7.12-7.02 (m,3H), 6.72 (d, 1H), 6.59 (d, 1H), 6.36 (d, 1H), 3.62 (br s, 4H), 3.13 (brs, 4H), 2.95-2.69 (m, 6H) 2.68-2.35 (m, 4H), 2.32-3.03 (m, 10H),2.02-1.84 (m, 4H), 1.42 (m, 6H), 0.94 (t, 6H)

EXAMPLE 3054-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 305A 5-bromo-6-chloropyridine-3-suIfonamide

5-Bromo-6-chloropyridine-3-sulfonyl chloride (8.2 g) in methanol (20 mL)was cooled to 0° C. To this solution was added 7N NH₃ in methanol (80mL). The reaction mixture was stirred overnight. The solvent was removedat low temperature, and the residue was partitioned between ethylacetate and water. The aqueous layer was extracted with ethyl acetatethree times. The combined organic layers were washed with brine, dried(MgSO₄), filtered, and concentrated. The residue was purified by flashcolumn chromatography on silica gel to give the product.

EXAMPLE 305B 6-((1,4-dioxan-2-yl)methoxy-5-bromopyridine-3-sulfonamide

(1,4-Dioxan-2-yl)methanol (211 mg) in tetrahydrofuran (10 mL) wastreated with 60% sodium hydride (125 mg). The reaction mixture wasstirred for 10 minutes. To this solution was added EXAMPLE 305A (211mg). The reaction mixture was stirred overnight. It was poured intowater, neutralized with 10% aqueous HCl, and extracted with ethylacetate three times. The combined organic layers were washed with brine,dried over MgSO₄, filtered, and concentrated to afford the product.

EXAMPLE 305C 6-((1,4-dioxan-2-yl)methoxy)-5-cyanopyridine-3-sulfonamide

A mixture of EXAMPLE 305B (100 mg), dicyanozinc (20 mg), andtetrakis(triphenylphosphine)palladium(0) (40 mg) inN,N-dimethylformamide (0.5 mL) was degassed via vacuum/nitrogen cyclethree times. The reaction mixture was heated at 120° C. for 3 hours.After cooling, it was poured into water and extracted with ethyl acetatethree times. The combined organic layers were washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was purified withflash column chromatography on silica gel eluting with 2%-5%methanol/dichloromethane to give the title compound.

EXAMPLE 305D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 305C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.14 (s, 1H), 8.76 (s, 1H), 8.55 (s, 1H), 7.57(d, 1H), 7.33 (m, 4H), 7.12 (d, 1H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.34(s, 1H), 6.14 (s, 1H), 4.44 (d, 2H), 3.91 (m, 1H), 3.80 (m, 2H), 3.63(m, 2H), 3.46 (m, 2H), 3.33 (m, 4H), 3.09 (m, 4H), 2.35 (m, 2H), 2.17(m, 2H), 1.98 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 306N-({[5-bromo-6-(1,4-dioxan-2ylmethoxy)pyridino-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 305B for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.19 (s, 1H), 8.58 (dd, 1H), 8.37 (d, 1H), 7.55(d, 1H), 7.35 (m, 4H), 7.26 (d, 1H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.40(s, 1H), 6.10 (d, 1H), 4.37 (m, 2H), 3.89 (m, 1H), 3.79 (m, 2H), 3.63(m, 2H), 3.47 (m, 2H), 3.31 (m,2H), 3.06 (m, 4H), 2.85 (m, 2H), 2.32 (m,2H), 2.14 (s, 2H), 1.96 (s, 2H), 1.38 (m, 2H), 0.91 (s, 6H).

EXAMPLE 307Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 307A Trans-5-bromo-6-((1r,4r)-4-morpholinocyclohexylamino)pyridine-3-sulfonamide

A mixture of EXAMPLE 305A (1.0 g) trans 4-morpholinocyclohexanamine(0.95 g) and triethylamine (3.08 mL) in anhydrous dixoane (20 mL) washeated at 110° C. overnight. The organic solvent was removed undervacuum. The residue was purified with flash column chromatography onsilica gel eluting with 2%-8% methanol/dichloromethane to give the titlecompound.

EXAMPLE 307BTrans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 307A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.20 (m, 1H), 8.43 (d, 1H), 8.05 (d, 1H), 7.55(d, 1H), 7.35 (m, 4H), 7.27 (d, 1H), 7.03 (d, 2H), 6.61 (dd, 1H), 6.49(dd, 1H), 6.40 (dd, 1H), 3.93 (m, 1H), 3.60 (m, 4H), 3.38 (m, 2H), 2.98(m, 4H), 2.70 (s, 2H), 2.60 (m, 4H), 2.34 (m, 1H), 2.15 (m, 6H), 1.92(d,6H), 1.37 (m, 6H), 0.92 (s, 6H).

EXAMPLE 3084-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 308A5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 296C for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 301A.

EXAMPLE 308B5-cyano-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 308A for EXAMPLE301A in EXAMPLE 301B.

EXAMPLE 308C4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 308B for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.15 (s, 1H), 8.79 (s, 1H), 8.59 (s, 1H), 7.57(d, 1H), 7.34-7.37 (m, 3H), 7.30 (d, 1H), 7.13 (d, 1H), 7.05 (d, 2H),6.64 (dd, 1H), 6.35 (s, 1H), 6.13 (s, 1H), 4.25 (d, 2H), 3.75-3.80 (m,2H), 3.56-3.62 (m, 2H), 3.09 (s, 4H), 2.15-2.60 (m, 4H), 1.80-21.83 (m,2H), 1.41 (d, 2H), 0.93 (s, 6H).

EXAMPLE 3092-(3-amino-5-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 309A2-(3-chloro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

1-Bromo-3-chloro-5-nitrobenzene (0.51 g), bis(pinacolato)diboron (0.60g), potassium acetate (0.63 g), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.09 g)were combined with dimethylformamide (5.3 mL), flushed with nitrogen,heated at 60° C. overnight, diluted with ethyl acetate, washed withwater and brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel with 5-10% ethyl acetate in hexanes aseluent to give the product.

EXAMPLE 309B 3-chloro-5-nitrophenol

EXAMPLE 309A (0.5 g) in tetrahydrofuran (10 mL) was treated with a 4 Naqueous solution of sodium hydroxide (2.65 mL), heated at 50° C. for 4hours, cooled to 0° C., treated dropwise with a 30% aqueous hydrogenperoxide solution (0.65 mL), stirred overnight while warming to roomtemperature and then quenched with saturated aqueous sodium thiosulfatesolution. The resulting mixture was partitioned between ethyl acetateand 1N aqueous sodium hydroxide solution and the organic portion was setaside. The aqueous layer was acidified to pH 4 with 2N aqueous HClsolution and extracted with ethyl acetate (2×100 mL). These extractswere combined, washed with brine, dried (MgSO₄), filtered, concentratedand chromatographed on silica gel with 5-10% ethyl acetate in hexanes aseluent to give the product.

EXAMPLE 309C methyl 2-(3-chloro-5-nitrophenoxy)-4-fluorobenzoate

The title compound was prepared by substituting methyl2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and EXAMPLE 309B for2-methyl-5-indolol in EXAMPLE 3A.

EXAMPLE 309D methyl 2-(3-amino-5-chlorophenoxy)-4-fluorobenzoate

EXAMPLE 309C (0.31 g) in a 1:1 mixture of methanol and tetrahydrofuran(9.5 mL) was treated with tin(II) chloride dihydrate (1.06 g), heated at65° C. for 4 hours and filtered through a pad of celite rinsing withethyl acetate. The filtrate was washed with water and brine, dried(MgSO₄), filtered, concentrated and chromatographed on silica gel with10-20% ethyl acetate in hexanes as eluent to give the product.

EXAMPLE 309E methyl2-(3-amino-5-chlorophenoxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared by substituting piperazine for EXAMPLE3F and EXAMPLE 309D for EXAMPLE 3A in EXAMPLE 3G.

EXAMPLE 309F1-chloro-4-(2-(chloromethyl)-5,5-dimethylcyclohex-1-enyl)benzene

EXAMPLE 3D (0.251 g) in tetrahydrofuran (5 mL) at 0° C. was treatedsequentially with N,N-diisopropylethylamine (0.524 mL) andmethanesulfonyl chloride (0.086 mL) and then stirred for 1.5 hours.Additional N,N-diisopropylethylamine (0.524 mL) and methanesulfonylchloride (0.086 mL) were added and stirring was continued for anotherhour. The reaction mixture was diluted with ethyl acetate, washed withwater and brine, dried (MgSO₄), filtered and concentrated. Theconcentrate was slurried in a 1:1 mixture of diethyl ether anddichloromethane and unreacted EXAMPLE 3D was removed by filtration. Thefiltrate was concentrated. The mixture was swirled with diethyl etherand the liquid decanted three times. The decanted diethyl ether mixturewas concentrated and dried under vacuum to give the product.

EXAMPLE 309G methyl2-(3-amino-5-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

EXAMPLE 309F (0.109 g) in N,N-dimethylformamide (2 mL) was treated withEXAMPLE 309E (0.15 g) and cesium carbonate (0.264 g), stirred at ambienttemperature over two nights, diluted with ethyl acetate, washed withwater and brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel with 0 to 5% acetone in dichloromethane aseluent to give the product.

EXAMPLE 309H2-(3-amino-5-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 309G for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 309I2-(3-amino-5-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl})piperazin-1-yl)-N-({3-nitro-4-[(tetrahydra-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 309H for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.42 (s,1H), 8.62 (t, 1H), 8.52 (d, 1H), 7.74 (dd, 1H), 7.48 (d, 1H), 7.36 (d,2H), 7.13 (d, 1H), 7.07 (d, 2H), 6.74 (dd, 1H), 6.41 (d, 1H), 6.22 (t,1H), 5.92 (m, 2H), 5.47 (s, 2H), 3.86 (dd, 2H), 3.32 (m, 4H), 3.18 (m,4H), 2.80 (m, 2H), 2.21 (m, 6H), 1.98 (s, 2H), 1.89 (m, 1H), 1.64 (dd,2H), 1.41 (t, 2H), 1.26 (m, 2H), 0.95 (s, 6H).

EXAMPLE 3104-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 310A 5-bromo-6-(2-morpholinoethoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting 2-morpholinoethanol for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 301A.

EXAMPLE 310B 5-cyano-6-(2-morpholinoethoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 310A for EXAMPLE301A in EXAMPLE 301B.

EXAMPLE 310C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 310B for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.14 (s, 1H), 8.75 (d, 1H), 8.52 (d, 1H), 7.58(d, 1H), 7.33-7.36 (m, 3H), 7.28 (d, 1H), 7.09 (d, 1H), 7.05 (d, 2H),6.62 (dd, 1H), 6.34 (s, 1H), 6.12 (s, 1H), 4.62 (t, 2H), 3.25-3.61 (m,4H), 3.05 (s, 4H), 2.93 (s, 4H), 2.68 (s, 4H), 2.32-2.36 (m, 4H), 2.15(s, 2H), 1.96 (s, 2H), 1.40 (d, 2H), 0.93 (s, 6H).

EXAMPLE 311Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 311A Trans-4-(4-aminocyclohexyloxy)-3-nitrobenzenesulfonamide

to a solution of tert-butyl 4-hydroxycyclohexylcarbamate (0.250 g) intetrahydrofuran (5 mL) was added sodium hydride (0.186 g). Afterstirring for 15 minutes, 4-fluoro-3-nitrobenzensulfonamide (0.256 g) wasadded as a solution in tetrahydrofuran (1 mL). The reaction was heatedto 60° C. for 1.5 hours, cooled and poured into a mixture ofdichloromethane (100 mL) and water (25 mL). The aqueous layer wasadjusted to pH˜4 with 1N aqueous HCl and the organic layer wasseparated, washed with brine (50 mL), dried over magnesium sulfate andconcentrated. The residue was loaded onto silica gel (GraceResolve 40 g)and eluted using a gradient of 0.5% to 7.5% methanol/dichloromethaneover 30 minutes. This solid was immediately treated with HCl (4.0 M indioxane, 5 mL) at room temperature for 1 hours and concentrated to givethe title compound.

EXAMPLE 311B

Trans-4-(4-morpholinocyclohexyloxy-3-nitrobenzenesulfonamide

To EXAMPLE 311A (0.220 g) and 1-bromo-2-(2-bromoethoxy)ethane (0.177 g)in N,N-dimethylformamide (3 mL) was added triethylamine (0.338 mL) andthe reaction heated to 70° C. for 5 hours. The reaction was cooled andthe resulting precipitate removed by filtration. The reaction wasconcentrated and loaded onto silica gel and eluted using a gradient of0.5% to 7.5% methanol/dichloromethane to give the title compound.

EXAMPLE 311CTrans-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(4-morpholinocyclohexyloxy)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 311B for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.21-11.09 (m, 1H), 8.29-8.13 (m, 2H),8.03-7.88 (m, 1H), 7.54 (s, 1H), 7.33 (d, 4H), 7.21-7.11 (m, 1H), 7.04(d, 2H), 6.97-6.89 (m, 1H), 6.66-6.51 (m, 1H), 6.43-6.31 (m, 1H), 6.08(s, 1H), 4.62-4.49 (m, 1H), 3.62 (s, 4H), 2.98 (s, 4H), 2.68 (d, 7H),2.19 (s, 8H), 1.95 (s, 4H), 1.38 (s, 6H), 0.92 (s, 6H).

EXAMPLE 312N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 312A5-bromo-6-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 49B for trans4-morpholinocyclohexanamine in EXAMPLE 307A.

EXAMPLE 312BN-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 312A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.16 (s, 1H), 8.40 (d, 1H), 8.05 (d, 1H), 7.56(d, 1H), 7.32 (m, 4H), 7.19 (m, 1H), 7.04 (d, 2H), 6.58 (d, 1H), 6.38(s, 1H), 6.05 (s, 1H), 4.05 (m, 1H), 3.93 (d, 2H), 3.24 (m, 8H), 2.96(m, 4H), 2.72 (m, 3H), 2.15 (m, 6H), 1.93 (m, 2H), 1.85 (m, 4H), 1.55(m, 2H), 1.38 (t, 2H), 1.17 (t, 2H), 0.91 (s, 6H).

EXAMPLE 3134-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamideEXAMPLE 313A2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE1F and EXAMPLE 296D for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 313B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 313A for EXAMPLE265E in EXAMPLE 267. ¹H NMR (500 MHz, methylene chloride-d₂) δ 8.44 (d,1H), 8.24 (dd, 1H), 7.86 (d, 1H), 7.71 (s, 1H), 7.24 (m, 3H), 7.19 (d,1H), 6.97 (d, 2H), 6.77 (d, 1H), 6.62 (d, 2H), 6.14 (d, 1H), 4.19 (d,2H), 3.84 (m, 2H), 3.75 (m, 2H), 3.39 (s, 2H), 3.14 (br.s, 4H), 2.77 (s,2H), 2.30-2.10 (m, 6H), 1.99 ((br.s, 2H), 1.95-1.87 (m, 4H), 1.55 (m,2H), 1.43 (t, 2H), 0.95 (s, 6H).

EXAMPLE 314Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideEXAMPLE 314A oxepan-4-one

Tetrahydro-2H-pyran-4-one (5 g) was placed in methanol (30 mL) in thepresence of barium oxide (0.85 g). Nitrosomethylurethane (6.6 g) wasadded slowly to the reaction mixture. During the addition, barium oxide(1.0 g) was added by small portions. The reaction mixture was stirred 3hours at room temperature and then filtrated. The methanol wasevaporated, diethyl ether was then added to the residue, and aprecipitate was formed. The mixture was filtrated and diethyl etherevaporated to afford the product.

EXAMPLE 314B (Z)-5-chloro-2,3,6,7-tetrahydrooxepine-4-carbaldehyde

Phosphorus oxychloride (3.45 mL) was added dropwise to a cooled (0° C.)solution of EXAMPLE 314A (4.2 g) in N,N-dimethylformamide (12 mL) anddichloromethane (30 mL). The mixture was then stirred at roomtemperature overnight before it was diluted with ethyl acetate (300 mL)and washed with aqueous sodium acetate, water (3×), brine and dried overNa₂SO₄. After filtration and concentration, the crude product was useddirectly in the next reaction without further purification.

EXAMPLE 314C(Z)-5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepine-4-carbaldehyde

To a mixture of 4-chlorophenylboronic acid (6.10 g), EXAMPLE 314B (5.2g), palladium(II) acetate (146 mg, 0.65 mmol), K₂CO₃ (13.5 g) andtetrabutylammonium bromide (10.5 g) was added water (200 mL). Themixture was stirred at 50° C. for 4 hours. The mixture was diluted withethyl acetate (400 mL) and washed with water (3×) and brine and driedover Na₂SO₄. After filtration and concentration, the residue was loadedon a column and eluted with 5 to 20% ethyl acetate in hexane to give thepure product.

EXAMPLE 314D (Z)-ethyl2-(6-chloro-1H-indol-5-yloxy)-4-(4-((5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLE 38E and EXAMPLE 38E with EXAMPLE 242F and EXAMPLE 314C.

EXAMPLE 314E(Z)-2-(6-chloro-1H-indol-5-yoxy)-4-(4-((5-(4-chlorophenyl)-2,3,6,70tetrahydrooxepin-4-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 38G by replacingEXAMPLE 34B with EXAMPLE 314D.

EXAMPLE 314FTrans-4-(4-morpholinocyclohexylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

The title compound was prepared by substituting trans4-morpholinocyclohexanamine for 3-(N-morpholinyl)-1-propylamine andEXAMPLE 131C for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 4A.

EXAMPLE 314GTrans-2-[(6-chloro)-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 314E and EXAMPLE 314F,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.38 (s, 1H),8.20 (m, 1H), 7.98 (dd, 1H), 7.53 (m, 4H), 7.38 (m, 3H), 7.13 (m, 3H),6.98 (m, 1H), 6.72 (m, 3H), 6.45 (d, 1H), 3.86 (m, 12H), 3.36 (m, 3H),3.02 (m, 6H), 2.74 (d, 8H), 2.18 (m, 4H), 1.65 (m, 2H).

EXAMPLE 315Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared in EXAMPLE 1H by replacing EXAMPLE 1Fand EXAMPLE 1G with EXAMPLE 314E and EXAMPLE 205A, respectively. ¹H NMR(300 MHz, dimethylsulfoxide-d₆) δ 11.09 (s, 1H), 8.38 (d, 1H), 8.01 (d,1H), 7.70 (dd, 1H), 7.57 (d, 1H), 7.46 (s, 1H), 7.34 (m, 3H), 7.07 (d,2H), 6.91 (m, 2H), 6.57 (m, 2H), 6.30 (s, 1H), 6.02 (d, 1H), 3.61 (m,10H), 2.98 (m, 12H), 2.28 (m, 8H), 1.95 (m, 4H), 1.36 (m, 2H).

EXAMPLE 3164-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 277B and EXAMPLE 184A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.18 (s, 1H),9.16 (s, 1H), 8.52 (d, 1H), 7.89 (dd, 1H), 7.56 (m, 2H), 7.31 (m, 5H),7.13 (d, 2H), 6.62 (dd, 1H), 6.39 (s, 1H), 6.07(d, 1H), 4.09 (m, 2H),2.95 (m, 9H), 2.81 (s, 2H), 2.35 (s, 3H), 2.16 (m, 6H), 1.18 (s, 6H).

EXAMPLE 3174-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 317A 4-morpholinobut-2-yn-1-ol

To a solution of morpholine (4.36 g) in toluene (15 mL) was added4-chlorobut-2-yn-1-ol (2.09 g) in toluene (5 mL). The solution wasstirred at 85° C. for 3 hours. After cooling, the solid was filteredoff. The filtrate was subjected to vacuum distillation to give the titlecompound.

EXAMPLE 317B 4-(4-morpholinobut-2-ynyloxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 317A for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 264A.

EXAMPLE 317C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 317B for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.12 (s, 1H), 8.39 (d, 1H), 8.14 (dd, 1H),7.52-7.54 (m, 2H), 7.34-7.39 (m, 3H), 7.32-7.35 (m, 3H), 7.29 (d, 1H),7.04 (d, 2H), 6.64 (dd, 1H), 6.41 (s, 1H), 6.09 (d, 1H), 5.16 (s, 2H),3.52-3.55 (m, 4H), 3.05 (s, 4H), 2.82 (s, 4H), 2.37-2.39 (m, 4H), 2.26(s, 4H), 1.95 (s, 2H), 1.39 (d, 2H), 0.92 (s, 6H).

EXAMPLE 3182-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 318A methyl 4-fluoro-2-(6-nitropyridin-3-yloxy)benzoate

To a solution of methyl 4-fluoro-2-hydroxybenzoate (23.5 g) and2-nitro-5-chloropyridine (21.9 g) in N,N-dimethylformamide (120 mL) wasadded cesium carbonate (45 g). The mixture was stirred at 50° C.overnight. The mixture was diluted with ethyl acetate (800 mL) andwashed with water (3×) and brine. After drying over Na₂SO₄ andfiltration, the solvent was evaporated under vacuum and the residue waspurified by silica gel chromatography (2% ethyl acetate indichloromethane) to give the title compound.

EXAMPLE 318B methyl 2-(6-aminopyridin-3-yloxy)-4-fluorobenzoate

EXAMPLE 318A (12.995 g) and methanol (150 mL) were added to Ra—Ni, waterwet A-7000 (6.50 g) in a 250 mL SS pressure bottle and stirred for 2hours at 30 psi and room temperature. The mixture was filtered through anylon membrane and concentrated to give the title compound.

EXAMPLE 318C Methyl 2-(6-amino-5-chloropyridin-3-yloxy)-4-fluorobenzoate

EXAMPLE 318B (3.0 g) and 1-chloropyrrolidine-2,5-dione (1.680 g) werestirred together in N,N-dimethylformamide (30 mL) at room temperatureunder nitrogen for 16 hours. The reaction was diluted with ethyl acetate(200 mL) and washed with water (75 mL), brine (75 mL), dried overmagnesium sulfate, filtered and concentrated. Silica gel chromatography(GraceResolv 80 g) eluting with a gradient of 5% to 35% ethylacetate/hexanes over 40 minutes (Flow=40 mL/min) gave the titlecompound.

EXAMPLE 318D methyl2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 318C for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 318E2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 318D for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 318F2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, CDCl₃) δ 9.86 (s, 1H), 8.89 (d, 1H),8.52 (t, 1H), 8.17 (dd, 1H), 7.96-7.83 (m, 2H), 7.36 (d, 1H), 7.23 (s,1H), 6.99-6.86 (m, 3H), 6.54 (dd, 1H), 5.97 (d, 1H), 4.95 (s, 2H), 4.01(d, 2H), 3.42 (d, 2H), 3.32-3.22 (m, 2H), 3.12 (s, 4H), 2.78 (s, 2H),2.22 (d, 6B), 1.99 (s, 2H), 1.72 (s, 2H), 1.50-1.34 (m, 5H), 0.96 (s,6H).

EXAMPLE 3194-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 319A 4-(1-Methanesulfonyl-piperidin-4-ylamino)-3-nitro-benzenesulfonamide

The title compound was prepared by substituting1-(methylsulfonyl)piperidin-4-amine for tert-butyl4-aminopiperidine-1-carboxylate in EXAMPLE 140A.

EXAMPLE 319B4-(4-{[2-(4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 319A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.21 (br s, 1H), 8.59 (d, 1H), 8.26 (d, 1H),7.89 (dd, 1H), 7.50 (d, 1H), 7.38 (t, 1H), 7.34 (d, 2H), 7.31 (t, 1H),7.28 (d, 1H), 7.22 (d, 1H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.40 (t, 1H),6.10 (d, 1H), 3.82 (m, 1H), 3.56 (dt, 2H), 3.09 (br s, 4H), 2.96 (dd,2H), 2.92 (s, 3H), 2.73 (m, 2H), 2.25-2.08 (m, 6H), 2.02 (dd, 2H), 1.95(br s, 2H), 1.70 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

EXAMPLE 320Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamideEXAMPLE 320ATrans-2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(4-morpholinocyclohexylamino)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE1F and EXAMPLE 205A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 320BTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 320A for EXAMPLE265E in EXAMPLE 267. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 10.37 (s,1H), 8.41 (s, 1H), 8.17 (d, 1H), 7.72 (d, 1H), 7.48 (d, 1H), 7.36 (d,2H), 7.13 (d, 1H), 7.06 (d, 2H), 6.95 (t, 1H), 6.74 (d, 1H), 6.44 (m,2H), 6.12 (d, 1H), 3.70-3.58 (m, 4H), 3.34 (m, 2H), 3.24 (s, 2H), 3.16(br.s, 4H), 2.79 (m, 6H), 2.25 (m, 3H), 2.18 (m, 3H), 2.12 (m, 2H), 1.98(m, 4H), 1.55-1.40 (m, 4H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 3214-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamideEXAMPLE 321A2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(2-methoxyethylamino)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 266D for EXAMPLE1F and EXAMPLE 263A for EXAMPLE 1G in EXAMPLE 1H.

EXAMPLE 321B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 321A for EXAMPLE265E in EXAMPLE 267. ¹H NMR (500 MHz, methylene chloride-d₂) δ 9.80(br.s, 1H), 8.73 (d, 1H), 8.56 (t, 1H), 8.00 (dd, 1H), 7.87 (d, 1H),7.76 (br.s, 1H), 7.25 (d, 2H), 7.22 (t, 1H), 7.96 (d, 2H), 6.94 (d, 1H),6.74 (d, 1H), 6.62 (m, 2H), 6.16 (d, 1H), 3.68 (t, 2H), 3.54 (t, 2H),3.41 (s, 3H), 3.37 (s, 2H), 3.13 (br.s, 4H), 2.77 (m, 2H), 2.30-2.18 (m,6H), 1.99 (br.s, 2H), 1.43 (t, 2H), 0.95 (s, 6H).

EXAMPLE 3224-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ytmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 322A6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-((triisopropylsilyl)ethynyl)pyridine-3-sulfonamide

EXAMPLE 301B (0.176 g), bis(triphenylphosphine)palladium(II) chloride(0.176 g), copper(I) iodide (0.010 g), N,N-dimethylacetamide (2.5 mL)and triethylamine (0.105 mL) were combined, flushed with nitrogen andstirred for 2 minutes. (Triisopropyl)acetylene (0.135 mL) was added andthe reaction mixture was flushed with nitrogen again, heated at 60° C.overnight, diluted with ethyl acetate, washed with water and brine,dried (MgSO₄), filtered, concentrated and chromatographed on silica gelwith 10-30% ethyl acetate in hexanes as eluent to give the product.

EXAMPLE 322B5-ethynyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 322A (0.205 g) in tetrahydrofuran (3 mL) at ambient temperaturewas treated with tetrabutyl ammonium fluoride (1 M in tetrahydrofuran)(0.906 mL) and stirred at ambient temperature for 4 hours. Additionaltetrabutyl ammonium fluoride (1 M in tetrahydrofuran) (1.8 mL) was addedand the mixture was heated at 40° C. for 45 minutes. Solid tetrabutylammonium fluoride (0.253 g) was added and heating was continued for 30minutes. The reaction mixture was concentrated and then chromatographedon silica gel using 0-2% methanol in dichloromethane as eluent to givethe product.

EXAMPLE 322C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 322B for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.21 (s, 1H), 8.62 (d, 1H), 8.22 (d, 1H), 7.53(d, 1H), 7.35 (m, 5H), 7.04 (d, 2H), 6.65 (dd, 1H), 6.41 (m, 1H), 6.08(s, 1H), 4.56 (s, 1H), 4.25 (d, 2H), 3.86 (dd, 2H), 3.35 (m, 2H), 3.05(m, 4H), 2.81 (m, 2H), 2.24 (m, 6H), 2.04 (m, 1H), 1.95 (s, 2H), 1.64(dd, 2H), 1.36 (m, 4H), 0.92 (s, 6H).

EXAMPLE 3234-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 277B for EXAMPLE1F and EXAMPLE 322B for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) δ 12.39 (s, 1H), 9.27 (d, 1H), 8.90 (d, 1H), 8.09 (d, 1H),7.52 (t, 1H), 7.46 (m, 4H), 7.10 (m, 2H), 6.68 (dd, 2H), 6.60 (m, 1H),6.50 (d, 1H), 4.49 (s, 1H), 4.38 (m, 2H), 4.22 (d, 2H), 3.95 (dd, 2H),3.29 (td, 2H), 2.98 (m, 4H), 2.82 (s, 2H), 2.21 (m, 2H), 2.09 (m, 4H),1.98 (m, 1H), 1.63 (dd, 2H), 1.42 (m, 2H), 1.29 (s, 6H).

EXAMPLE 324Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 205A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.45-10.43 (m, 1H), 8.56 (d, 1H), 8.20 (d, 1H),7.86 (d, 1H), 7.73 (d, 1H), 7.44 (d, 1H), 7.35 (d, 3H), 7.23 (d, 1H),7.06 (d, 2H), 6.64 (d, 1H), 6.16 (d, 3H), 3.70 (s, 5H), 3.11 (s, 4H),2.77 (s, 6H), 2.10 (d, 12H), 1.43 (d, 6H), 0.94(s, 6H).

EXAMPLE 3254-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 325A 1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ol

Piperidin-4-ol (7.8 g) and dihydro-2H-pyran-4(3H)-one (5.0 g) weredissolved in titanium(IV) isopropoxide (30 mL) and the reaction wasstirred at room temperature overnight. Next day methanol (40 mL) wasadded and the reaction was cooled to 0° C. Then NaBH₄ (3.8 g) was addedin portions over one hour. After two hours 1N aqueous NaOH was added,followed by ethyl acetate addition. After filtration through celite thelayers were separated, the aqueous layer extracted with ethyl acetate,and the combined organic layers were dried over Na₂SO₄. The crudematerial was purified by column chromatography using CH₂Cl₂ having 5-10%7N NH₃ in methanol.

EXAMPLE 325B5-chloro-6-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yloxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 303A for EXAMPLE305A and EXAMPLE 325A for (1,3-dioxan-4-yl)methanol in EXAMPLE 305B.

EXAMPLE 325C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE122C and EXAMPLE 325B for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.06 (s, 1H), 8.64 (s, 1H), 8.37 (s, 1H), 7.60(d, 1H), 7.35 (d, 2H), 7.28 (s, 1H), 7.24 (d, 1H), 7.04 (d, 2H), 6.96(d, 1H), 6.55 (d, 1H), 6.27 (s, 1H), 6.09 (s, 1H), 5.20 (m, 1H), 3.90(d, 2H), 3.30 (m, 5H), 2.96 (br m, 6H), 2.72 (s, 2H), 2.19 (br m, 6H),2.00 (m, 2H), 1.95 (s, 2H), 1.78 (br m, 4H), 1.47 (br m, 2H), 1.39 (t,2H), 0.92 (s, 6H).

EXAMPLE 326N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 326A5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 303A for EXAMPLE305A and EXAMPLE 296C for (1,3-dioxan-4-yl)methanol in EXAMPLE 305B.

EXAMPLE 326BN-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE122C and EXAMPLE 326A for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.18 (s, 1H), 8.75 (s, 1H), 8.27 (s, 1H), 7.55(d, 1H), 7.34 (m, 4H), 7.23 (br d, 1H), 7.04 (d, 2H), 6.84 (dd, 1H),6.40 (s, 1H), 6.09 (s, 1H), 4.53 (d, 2H), 3.77 (m, 2H), 3.60 (m, 2H),3.06 (v br s, 4H), 2.82 (br s, 2H), 2.27 (v br s, 4H), 2.15 (br m, 2H),1.95 (s, 2H), 1.85 (m, 4H), 1.40 (t, 2H), 0.92 (s, 6H).

EXAMPLE 3274-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was pre3pared as described in EXAMPLE 1H by replacingEXAMPLE 1F and EXAMPLE 1G with EXAMPLE 154E and EXAMPLE 65A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.21 (s, 1H),8.57 (d, 1H), 8.24 (d, 1H), 7.87 (dd, 1H), 7.50 (d, 1H), 7.33 (m, 5H),7.18 (d, 1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.40 (s, 1H), 6.09 (s, 1H),3.70 (m, 1H), 2.98 (m, 6H), 2.73 (s, 2H), 2.23 (m, 6H), 1.93 (m, 4H),1.76 (m, 1H), 1.57 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H), 0.43 (m, 5H).

EXAMPLE 3284-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 328A (4-ethylmorpholin-3-yl)methanol

Morpholin-3-ylmethanol (500 mg) and iodoethane (666 mg) inN,N-dimethylformamide was treated with K₂CO₃ (1.1 g) overnight. Thereaction mixture was diluted with water and extracted with ethylacetate. The organic layer was dried over Na₂SO₄ and concentrated toprovide the title compound.

EXAMPLE 328B4-((4-ethylmorpholin-3-yl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared as described in EXAMPLE 285A byreplacing (1,4-dioxan-2-yl)methanol with EXAMPLE 328A.

EXAMPLE 328C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared as described in EXAMPLE 110F byreplacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 154E and EXAMPLE328B, respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.21 (s,2H), 8.37 (d, 1H), 8.10 (dd, 1H), 7.52 (t, 2H), 7.37 (t, 1H), 7.31-7.36(m, 3H), 7.26 (d, 1H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.40 (s, 1H), 6.09(d, 1H), 4.43 (dd, 1H), 4.24 (dd, 1H), 3.80 (dd, 1H), 3.64-3.74 (m, 1H),3.49-3.61 (m, 2H), 3.03 (s, 4H), 2.92 (s, 1H), 2.78 (s, 4H), 2.52-2.60(m, 1H), 2.45 (s, 1H), 2.23 (s, 4H), 2.14 (s, 2H), 1.95 (s, 2H), 1.38(t, 2H), 1.00 (t, 3H), 0.92 (s, 6H).

EXAMPLE 3294-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]benzamideEXAMPLE 329A (S)-tert-butyl1-(tetrahydro-2H-pyran-4-yl)piperidin-3-ylcarbamate

The title compound was prepared by substitutingdihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde and(S)-tert-butylpiperidin-3-ylcarbamate for tert-butylpiperazine-1-carboxylate on EXAMPLE 1A.

EXAMPLE 329B (S)-1-(tetrahydro-2H-pyran-4-yl)piperidin-3-amine

The title compound was prepared by substituting EXAMPLE 329A for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 329C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 329B for2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol in EXAMPLE 240B. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ 8.92 (br s, 1H), 8.58 (br s, 1H), 7.85 (m,1H), 7.52 (d, 1H), 7.37 (m, 1H), 7.33 (m, 3H), 7.28 (br s, 1H), 7.10 (brs, 1H), 7.03 (d, 2H), 6.65 (m, 1H), 6.40 (br s, 1H), 6.08 (m, 1H), 3.98(br s, 1H), 3.90 (m, 2H), 3.27 (m, 2H), 3.01 (m, 4H), 2.77 (m, 4H), 2.60(m, 2H), 2.16 (m, 6H), 1.94 (m, 2H), 1.64 (m, 5H), 1.50 (m, 3H), 1.38(m, 2H), 1.23 (m, 1H), 0.94 (s, 6H).

EXAMPLE 3302-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 296D for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,CDCl₃) δ 9.88 (s, 1H), 8.58 (d, 1H), 8.38 (dd, 1H), 7.91 (t, 2H), 7.36(d, 1H), 7.29-7.11 (m, 3H), 6.94 (d, 2H), 6.62-6.47 (m, 1H), 5.96 (s,1H), 4.96 (s, 2H), 4.19 (d, 2H), 3.81 (dt, 4H), 3.13 (s, 4H), 2.78 (s,2H), 2.22 (d, 6H), 2.07-1.78 (m, 6H), 1.44 (s, 2H), 0.97 (d, 6H).

EXAMPLE 3314-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 331A 3-nitro-4-dioxidothiomorpholinoamino)benzenesulfonamide

The title compound was prepared by substituting4-aminothiomorpholine-1,1-dioxide for 3-(N-morpholinyl)-1-propylamine inEXAMPLE 4A.

EXAMPLE 331B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 331A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.22 (s, 1H), 9.65 (s, 1H), 8.56 (d, 1H), 7.88(m, 2H), 7.51 (d, 1H), 7.35 (m, 5H), 7.03 (d, 2H), 6.64 (dd, 1H), 6.41(d, 1H), 6.07 (d, 1H), 3.46 (m, 4H), 3.18 (m, 4H), 3.02 (m, 4H), 2.73(s, 2H), 2.15 (m, 6H), 1.95 (s, 2H), 1.38 (t, J=6.15 Hz, 2H), 0.92 (s,6H).

EXAMPLE 3324-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 332A3-nitro-4-((tetrahydrofuran-3-yl)methylamino)benzenesulfonamide

The title compound was prepared by substituting2-aminomethyl-tetrahydrofuran for 3-(N-morpholinyl)-1-propylamine inEXAMPLE 4A.

EXAMPLE 332B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 332A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.30 (br.s, 1H), 11.23 (s, 1H), 8.66 (t, 1H),8.59 (d, 1H), 7.87 (dd, 1H), 7.50 (d, 1H), 7.38 (t, 1H), 7.34 (m, 3H),7.30 (d, 1H), 7.16 (d, 1H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.41 (s, 1H),6.10 (s, 1H), 3.80 (q, 1H), 3.70 (t, 1H), 3.63 (q, 1H), 3.51 (dd, 1H),3.40 (m, 2H), 3.06 (br.s, 4H), 2.80 (m, 2H), 2.58 (m, 2H), 2.35-2.10 (m,5H), 2.00-1.90 (m, 3H), 1.65 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H).

EXAMPLE 333Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 333A trans-4-morpholinocyclohexanol

Trans-4-aminocyclohexanol (0.5 g), 1-bromo-2-(2-bromoethoxy)ethane (1.07g) and triethylamine (2.42 mL) were dissolved in anhydrous acetonitrile(20 mL). The reaction mixture was heated at 60° C. overnight. Theorganic solvent was removed under vacuum. The residue was purified byflash column chromatography on silica gel eluting with 7-10% methanol indichloromethane to give the title compound.

EXAMPLE 333BTrans-5-bromo-6-(4-morpholinocyclohexyloxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 333A for(1,4-dioxan-2-yl)methanol in EXAMPLE 305B.

EXAMPLE 333CTrans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 333B for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.15 (s, 1H), 8.51 (d, 1H), 8.30 (d, 1H), 7.57(d, 1H), 7.33 (m, 4H), 7.18 (d, 1H), 7.05 (d, 2H), 6.60 (dd, 1H), 8.37(s, 1H), 6.07 (d, 1H), 5.02 (m, 1H), 3.68 (m, 4H), 2.99 (m, 4H), 2.74(m, 7H), 2.23 (m, 8H), 1.95 (m, 4H), 1.41 (m, 6H), 0.92 (s, 6H).

EXAMPLE 334Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 334A tert-butyl(trans)-4-(dicyclopropylamino)cyclohexylcarbamate

A suspension of tert-butyl (trans)-4-aminocyclohexylcarbamate (1 g),molecular sieves 3A (1 g), acetic acid (2.67 mL),(1-ethoxycyclopropoxy)trimethylsilane (3.74 mL) and sodiumcyanoborohydride (0.880 g) in dry methanol (10 mL) was heated at refluxfor 3 hours. The insolubles were filtered off, the resulting solutionwas basified with aqueous NaOH (6 M) to pH 14, and extracted with ether.The combined extracts were washed with brine, dried and concentrated.The residue was purified by flash chromotography (silica gel 80 g,30-100% acetone/hexanes) providing the product.

EXAMPLE 334B (trans)-N′,N′-dicyclopropylcyclohexane-1,4-diaminebis(2,2,2-trifluoroacetate)

The title compound was prepared by substituting EXAMPLE 334A for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 334CTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

A suspension of EXAMPLE 240A (0.14 g), EXAMPLE 334B (0.110 g) andN,N-diisopropylethylamine (0.303 mL) in dioxane (3 mL) was stirred for 3days at 100° C. The mixture was concentrated and purified by RP HPLC(C8, 30%-100% CH₃CN/water/0.1% TFA). ¹H NMR (500 MHz, pyridine-d₅) δ12.38 (s, 1H), 9.31 (d, 1H), 8.48 (dd, 1H), 8.38 (d, 1H), 8.15 (d, 1H),7.47-7.53 (m, 3H), 7.41-7.46 (m, 3H), 7.01-7.08 (m, 3H), 6.72 (dd, 1H),6.54-6.59 (m, 2H), 3.45 (ddd, 1H), 3.01-3.07 (m, 4H), 2.72-2.79 (m, 3H),2.24 (t, 2H), 2.10 (d, 6H), 2.00-2.06 (m, 2H), 1.96 (s, 2H), 1.88 (d,2H), 1.67 (qd, 2H), 1.34-1.40 (m, 2H), 1.20-1.29 (m, 2H), 0.93 (s, 6H),0.48 (d, 8H).

EXAMPLE 335Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]benzamideEXAMPLE 335A tert-butyl(trans)-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexylcarbamate

The title compound was prepared by substituting tert-buty(trans)-4-aminocyclohexylcarbamate for tert-butylpiperazine-1-carboxylate and dihydro-2H-pyran-4(3H)-one for4′-chlorobiphenyl-2-carboxyldehyde in EXAMPLE 1A.

EXAMPLE 335B(trans)-N′-(tetrahydro-2H-pyran-4-yl)cyclohexane-1,4-diaminebis(2,2,2-trifluoroacetate)

The title compound was prepared by substituting EXAMPLE 335A for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 335CTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 335B for EXAMPLE334B in EXAMPLE 334C. ¹H NMR (500 MHz, pyridine-d₅) δ 12.35 (s, 1H),9.30 (d, 1H), 8.40 (dd, 1H), 8.35 (d, 1H), 8.19 (d, 1H), 7.51 (dd, 2H),7.46-7.49 (m, 2H), 7.43 (d, 2H), 7.05 (d, 2H), 6.92 (d, 1H), 6.73 (dd,1H), 6.54-6.59 (m, 2H), 3.99-4.04 (m, 2H), 3.45-3.52 (m, 1H), 3.41 (t,2H), 3.10(s, 1H), 3.01-3.07 (m, 4H), 2.91 (s, 1H), 2.75 (s, 2H),2.21-2.26 (m, 2H), 2.11 (d, 5H), 2.08 (d, 3H), 1.96 (s, 4H), 1.59 (s,2H), 1.54 (d, 2H), 1.30-1.40 (m, 4H), 0.93 (s, 6H).

EXAMPLE 336Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]benzamideEXAMPLE 336A tert-butyl4-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate

To a solutuion of tert-butyl piperazine-1-carboxylate (5.15 g) anddihydro-2H-pyran-4(3H)-one (3.05 g) stirred for 24 hours at roomtemperature in titanium (IV) isopropoxide (16.20 mL), methanol (5 mL)was added followed by careful addition of sodium borohydride (2.092 g).The reaction mixture was quenched with water/NaOH solution, extractedwith ether, dried over magnesium sulftate, filtered, and concentrated toyield the product. The crude product was used in the next step.

EXAMPLE 336B 1-(tetrahydro-2H-pyran-4-yl)piperazine dihydrochloride

To a solution of EXAMPLE 336A (3.92 g) in ether was added HCl (25 mL, 2M in ether) and the reaction mixture was stirred for 16 hours at roomtemperature. The solid product was filtered off, dried and used in nextstep without further purification.

EXAMPLE 336C Trans-tert-butyl4-(4-tetrahydro-2H-pyran-4-yl)piperazin-1-yl)cyclohexylcarbamate

To a solution of EXAMPLE 336B (1 g) and tert-butyl4-oxocyclohexylcarbamate (0.877 g) stirred for 24 hours at roomtemperature in titanium (IV) isopropoxide (2.410 mL), methanol (2 mL)was added followed by careful addition of sodium borohydride (0.311 g).The reaction mixture was quenched with water, extracted with ether,dried and concentrated. The crude product was purified by flashchromotography (silica 80 g, 50%-100% acetone/hexanes) providing theproduct.

EXAMPLE 336Dtrans-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)cyclohexanaminetris(2,2,2-trifluoroacetate)

The title compound was prepared by substituting EXAMPLE 336C for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 336E

Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 336D for EXAMPLE334B in EXAMPLE 334C. ¹H NMR (500 MHz, pyridine-d₅) δ 12.38 (s, 1H),9.30-9.34 (m, 1H), 8.41-8.46 (m, 1H), 8.37 (d, 1H), 8.13 (d, 1H),7.48-7.53 (m, 3H), 7.41-7.46 (m, 3H), 7.04 (d, 2H), 6.96 (t, 1H),6.69-6.74 (m, 1H), 6.54-6.59 (m, 2H), 3.99-4.05 (m, 2H), 3.29 -3.36 (m,2H), 3.05 (s, 4H), 2.74 (s, 2H), 2.62 (s, 5H), 2.57 (s, 3H), 2.27-2.36(m, 2H), 2.19 -2.27 (m, 3H), 2.11 (s, 6H), 1.96 (s, 2H), 1.91 (s, 1H),1.87 (s, 1H), 1.70 (s, 2H), 1.64 (s, 1H), 1.56 (td, 2H), 1.35-1.43 (m,4H), 1.29 (s, 2H), 0.93 (s, 6H).

EXAMPLE 3374-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 337A (4-fluorotetrahydro-2H-pyran-4-yl)methy 1 methanesulfonate

A mixture of EXAMPLE 296C (1.4 g), methanesulfonyl chloride 1.054 mL),triethylamine (2.99 mL), and 4-(dimethylamino)pyridine (0.051 g)inCH₂Cl₂ (20 mL) was stirred at 0° C. for 2 hours, concentrated andcromatographed on silica gel with 30% ethyl acetate in hexanes as eluentto give the product.

EXAMPLE 337B2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindoline-1,3-dione

A mixture of EXAMPLE 337A (1.8 g) and potassium phthalimide (2.356 g) inN,N-dimethylformamide (30 mL) was heated at 150° C. overnight, dilutedwith ethyl acetate, washed with water and brine, dried (MgSO₄),filtered, concentrated and chromatographed on silica gel with 30% ethylacetate in hexanes as eluent to give the product.

EXAMPLE 337C (4-fluorotetrahydro-2H-pyran-4-yl)methanamine

A mixture of EXAMPLE 337B (1.4 g) and hydrazine (1.548 mL) in ethanol(40 mL) was heated at 70° C. overnight, cooled to room temperature,slurried with CH₂Cl₃ (200 mL) and the solid removed by filtration. Thefiltrate was concentrated and chromatographed on silica gel with 100:5:1ethyl acetate/methanol/NH₄OH as eluent to give the product.

EXAMPLE 337D4-((4-fluorotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide

A mixture of 4-fluoro-3-nitrobenzenesulfonamide (0.44 g), EXAMPLE 337C(0.266 g), and triethylamine (1.11 mL) in tetrahydrofuran (10 mL) washeated at 70° C. overnight, diluted with ehtyl acetate, washed withwater and brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel with 50% ethyl acetate in hexanes aseluent to give the product.

EXAMPLE 337E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 337D for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.21 (m, 2H), 8.63 (t, 1H), 8.59 (d, 1H), 7.88(dd, 1H), 7.51 (d, 1H), 7.33 (m, 6H), 7.03 (m, 2H), 6.65 (dd, 1H), 6.40(m, 1H), 6.09 (d, 1H), 3.74 (m, 4H), 3.52 (m, 2H), 3.03 (m, 4H), 2.74(m, 2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.80 (m, 4H), 1.38 (t, 2H), 0.92(s, 6H).

EXAMPLE 338Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

A mixture of EXAMPLE 240A (153 mg), trans-4-(aminomethyl)cyclohexanol(73.5 mg) and N-ethyl-N-isopropylpropan-2-amine (0.16 mL) in dioxane (2mL) was heated at 100° C. for 20 hours and concentrated. The residue wasdissolved in dimcethylsulfoxide-methanol (1:1) and purified by HPLC,eluting with 40%-65% acetonitrile 0.1% TFA water over 40 minutes toprovide the title compound. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ11.22 (s, 2H), 8.56-8.62 (m, 2H), 7.85 (dd, 1H), 7.51 (d, 1H), 7.38 (t,1H), 7.29-7.36 (m, 4H), 7.12 (d, 1H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.41(s, 1H), 6.09 (d, 1H), 4.51 (d, 1H), 3.24 (t, 2H), 3.03 (s, 4H), 2.74(s, 2H), 2.16 (d, 6H), 1.95 (s, 2H), 1.83 (d, 2H), 1.74 (d, 2H), 1.56(dd, 1H), 1.38 (t, 2H), 0.95-1.16 (m, 4H), 0.92 (s, 6H).

EXAMPLE 3394-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 339A methyl 2-(1H-indol-4-yloxy)-4-fluorobenzoate

Methyl 2,4-difluorobenzoate 1.53 g), K₃PO₄ (1.89 g) and 4-hydroxyindole(1.08 Mg) were stirred at 110° C. in diglyme (12 mL) for 24 hours. Thereaction was cooled and poured into ether. The solution was washed threetimes with 1 M aqueous NaOH solution, and brine, and dried over Na₂SO₄.The solution was then concentrated, and the crude product waschromatographed on silica gel with 20% ethylacetate/hexanes.

EXAMPLE 339B methyl 2-(1H-indol-4-yloxy)-4-(piperazin-1-yl)benzoate

EXAMPLE 339A (1425 mg), piperazine (452 mg), and HK₂PO₄ (958 mg) werestirred in dimethylsuifoxide (20 mL) at 140° C. for 24 hours. Thereaction was diluted with ethylacetate, washed three times with water,washed with brine, dried over Na₂SO₄, and concentrated. The crudeproduct was chromatographed on silica gell with a methanol/methylenechloride gradient.

EXAMPLE 339C methyl2-(3-bromo-1H-indol-4-yloxy)-4-(piperazin-1-yl)benzoate

A solution of EXAMPLE 339B (1 g) in dichloromethane (50 mL) andN,N-dimethylformamide (5 mL) was cooled in an ice bath,N-bromosuccmimide (0.582 g) was added and the mixture was stirredovernight while warming to ambient temperature. The reaction wasconcentrated and the crude product was chromatographed on silica gelwith a methanol/methylene chloride gradient

EXAMPLE 339D tert-butyl3-bromo-4-(5-(4-(tert-butyloxycarboayl)piperazin-1-yl)-2-(methoxycarbonyl)phenoxy)-1H-indol-1-carboxylate

EXAMPLE 339C (388 mg) and di-tert-buty dicarbonate (590 mg) weredissolved in a mixture of acetonitrile (20 mL)and dichloromethane (20mL) N-ethyl-N-isopropylporpan-2-amine (0.165 mL) was added followed byN, N-dimethylpyridin-4-amine (33.0 mg) and the mixture wasstirred 18hours. The reaction was concentrated and the crude product was purifiedon a plug of silica gel with 15% ethyl acetate in hexane.

EXAMPLE 339E E (E)-tert-butyl4-(3-(3-(3-(dimethylamino)prop-1-enyl)-1H-indol-4-yloxy)-4-(methoxycarbonyl)phenyl)piperizine-1-carboxylate

A mixture EXAMPLE 339D (175 mg),(E)-N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-amine(103 mg), sodium carbonate (73.5 mg) andbis(triphenylphosphine)palladium(Il) dichloride (9.74 mg) in a mixtureof 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) was heated in a CEMDiscover microwave reactor at 150° C. for 30 minutes. The reaction waspartitioned between brine and ethyl acetate. The organic layer was driedover sodium sulfate, filtered and concentrated. The crude product waspurified on silica gel with a 7N methanolic ammonia/methylene chloridegradient.

EXAMPLE 339F tert-butyl4-(3-(3-(3-(dimethylamino)propyl)-1H-indol-4-yloxy)-4-(methoxycarbonyl)phenyl)piperizine-1-carboxylate

A mixture of EXAMPLE 339E (715 mg) and 5% palladium on carbon (143 mg)in methanol (20 mL) was hydrogenated at 30 psi for 16 hours at ambienttemperature. The reaction mixture was filtered, concentratedand thecrude product was chromatographed on silica gel with 7 N-methanolicammonia in methylene chloride.

EXAMPLE 339G methyl2-(3-(3-(dimethylamino)propyl)-1H-indol-4-yloxy)-4-(piperazin-1-yl)benzoate

A solution of EXAMPLE 339F (484 mg) in dichloromethane (22 mL) wascooled in an ice bath and 2,2,2-trifluoroacetic acid (11 mL) was added.The reaction was stirred for 2 hours, concentratedand the crude productwas chromatographed on silica gel with 7 N-methanolic ammonia inmethylene chloride.

EXAMPLE 339H methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-(3-(dimethylamino)propyl)-1H-indol-4-yloxy)benzoate

To a solution of EXAMPLE 339G (285 mg) and EXAMPLE 60D (171 mg) indichloromethane (20 mL) was added sodium triacetoxyborohydride (208 mg)portion wise over a few minutes. The reaction was stirred 72 hotsrs atambient temperature, quenched by the slow addition of saturated aqueoussodium bicarbonate solution (100 mL) and extracted with methylenechloride (75 mL). The organic layer was dried over sodium sulfate,filtered and concentrated. The crude product was purified on silica gelwith 7N-methanoic ammonia in methylene chloride.

EXAMPLE 339I4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-(3-(dimethylamino)propyl)-1H-indol-4-yloxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 399B for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 399J4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 339I for EXAMPLE1F EXAMPLE 1H. ¹H NMR (500 MHz, pyridine-d₅) δ 12.00 (s, 1H), 9.24 (s,1H), 8.49 (m, 1H), 8.43 (d, 1H), 8.37 (d, 1H), 7.45 (m, 2H), 7.25 (m,2H), 7.11 (d, 2H), 7.00 (t, 1H), 6.81 (m, 3H), 6.63 (d, 1H), 3.96 (d,2H), 3.30 (t, 2H), 3.06 (m, 10H), 2.82 (m, 7H), 2.49 (m, 2H), 2.24 (m,5H), 1.99 (m, 1H), 1.76 (m, 1H), 1.55 (m, 2H), 1.41 (m, 2H), 1.25 (m,4H), 0.96 (m, 6H), 0.84 (m, 2H).

EXAMPLE 3404-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 339I for EXAMPLE1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,pyridine-d₅) δ 11.98 (s, 1H), 9.19 (d, 1H), 8.97 (s, 1H), 8.48 (m, 1H),8.42 (m, 1H), 7.63 (d, 1H), 7.46 (d, 2H), 7.25 (m, 2H), 7.11 (d, 2H),7.00 (m, 1H), 6.80 (m, 2H), 6.64 (m, 1H), 3.04 (m, 8H), 2.82 (m, 10H),2.49 (m, 3H), 2.28 (m, 3H), 2.22 (m, 6H), 2.16 (m, 3H), 2.08 (m, 1H),1.99 (m, 2H), 1.40 (t, 2H), 0.96 (m, 6H), 0.84 (m, 2H).

EXAMPLE 3414-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 341A tert-butyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate

1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.0 g) intetrahydrofuran (5 mL) was treated with 1.0 N LiAlH₄ (2.54 mL) at 0° C.The reaction mixture was stirred at room temperature for 2 hours. Water(0.6 mL) was added to the reaction mixture drop-wise, followed by 2 Naqueous NaOH (0.2 mL). The reaction was stirred for another 1 hour. Thesolid was removed by filtration via a pack of Celite and washed withethyl acetate. The filtrate was washed with brine, dried over MgSO₄,filtered, and concentrated to give the product.

EXAMPLE 341B tert-butyl4-fluoro-4-((2-nitro-4-sulfamoylphenoxy)methyl)piperidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 341A for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 264A.

EXAMPLE 341C4-((4-fluoropiperidin-4-yl)methoxy)-3-ntirobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 341B for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 341D4-((1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

To EXAMPLE 341C (0.24 g) in methanol (3 mL) was added 3 Å molecularsieves (0.1 g), followed sequentially by acetic acid (0.31 mL),(1-ethoxycyclopropoxyl)trimethylsilane (0.64 mL), and sodiumcyanoborohydride (0.148 g). The reaction was heated under refluxovernight. After cooling, the reaction mixture was loaded onto a silicagel column. After drying, the column was eluted with 100:2:0.2 ethylacetate/methanol/NH₄OH to give the title compound.

EXAMPLE 341E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 341l D for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.20 (s, 1H), 8.37 (d, 1H), 8.10 (d, 1H), 7.53(d, 1H), 7.44 (d, 1H), 7.32-7.37 (m, 4H), 7.24 (d, 1H), 7.04 (d, 2H),6.63 (dd, 1H), 6.39 (s, 1H), 6.09 (d, 1H), 4.34 (d, 2H), 3.05 (s, 4H),2.90 (s, 2H), 2.78 (s, 2H), 2.14-2.26 (m, 6H), 1.68-1.82 (m, 4H), 1.38(d, 2H), 0.92 (s, 6H), 0.40-0.49 (m, 4H).

EXAMPLE 3424-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[1-(4-methoxybenzyl)-1H-1,2,3-benzotriazol-4-yl]oxy}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 342A 4-(tert-Butyl-dimethyl-silanyloxy)-1H-benzotriazole

To 4-hydroxybenzotriazole (5.000 g) in tetrahydrofuran (250 mL) wasadded sodium hydride (60% , 0.932 g). The solution was stirred at roomtemperature for 20 minutes, cooled to 0° C.,tert-butyldimethylchlorosilane (5.860 g) was added, the solution wasallowed to warm to room temperature, and stirred for 16 hours.Additional sodium hydride (60% , 0.500 g) was added, the solutionstirred for 15 minutes, additional tert-butyldimethylchlorosilane (3.000g) was added, and the solution stirred for three hours at roomtemperature. The solution was then added to saturated aqueous ammoniumchloride and extracted with ethyl acetate. The organic extract waswashed with brine, dried over anhydrous sodium sulfate, filtered,concentrated and purified by flash column chromatography on silica gelusing 20-30% ethyl acetate in hexanes.

EXAMPLE 342B4-(tert-Butyl-dimethyl-silanyloxy)-1-(4-methoxy-benzyl)-1H-benzotriazole

To EXAMPLE 342A (2.00 g) in dimethylformamide (40 mL) was added sodiumhydride (60% , 0.353 g). The solution was mixed for 10 minutes at roomtemperature and 4-methoxybenzylchloride (1.382 g) was added. Thesolution was heated at 80° C. for 16 hours, cooled, added to water, andextracted with 50% ethyl acetate in hexanes. The extract was washed withbrine, dried over anhydrous sodium sulfate, filtered, concentrated, andpurified by flash column chromatography on silica gel using 10% ethylacetate in hexanes.

EXAMPLE 342C 1-(4-Methoxy-benzyl)-1H-benzotriazol-4-ol

To a solution of EXAMPLE 342B (2.59 g) in tetrahydrofuran (40 mL) wasadded tetraammonium fluoride (1M in tetrahydrofuran 21.03 mL). Thesolution was mixed at room temperature for two hours. The solvent wasremoved under vacuum, the residue was taken up in ethyl acetate, and thesolution was vacuum filtered over a pad silica gel. The filtrate wasconcentrated and purified by flash column chromatography on silica gelusing 35% ethyl acetate in hexanes.

EXAMPLE 342D4-Fluoro-2-[1-(4-methoxy-benzyl)-1H-benzotriazol-4-yloxy]-benzoic acidmethyl ester

To a solution of EXAMPLE 342C (990 mg) and methyl 2,4-difluorobenzoate(734 mg) in diglyme (40 mL) was added potassium tert-butoxide (1M intetrahydrofuran, 4.07 mL). The solution was heated to 100° C. for 16hours, cooled, added to saturated ammonium chloride, and extracted with70% ethyl acetate in hexanes. The extract was washed with brine, driedover anhydrous sodium sulfate, filtered, concentrated and purified byflash column chromatography on silica gel using 30% ethyl acetate inhexanes.

EXAMPLE 342E2-[1-(4-Methoxy-benzyl)-1H-benzotriazol-4-yloxy]-4-piperzin-1-ylbenzoicacid methyl ester

To a solution of EXAMPLE 342D (650 mg) in dimethylsulfoxide (12 mL) wasadded piperazine (618 mg). The solution was heated at 100° C. for onehour, cooled, added to dichloromethane, extracted with water threetimes, dried over anhydrous sodium sulfate, filtered, and the solventwas removed under vacuum.

EXAMPLE 342F4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-[1-(4-methoxy-benzyl)-1H-benzotriazol-4-yloxy]-benzoicacid methyl ester

The title compound was prepared by susbtituting EXAMPLE 60D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 342E fortert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 342G4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperszin-1-yl}-2-[1-(4-methoxy-benzyl)-1H-benzotriazol-4-yloxy]-benzoicacid

The title compound was prepared by substituting EXAMPLE 342F for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 342H4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[1-(4-methoxybenzyl)-1H-1,2,3-benzotriazol-4-yl]oxy}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 342G for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.59 (t, 1H),8.37 (d, 1H), 7.67 (d, 1H), 7.56 (d, 1H), 7.38-7.23 (m, 3H), 7.30 (d,2H), 7.23 (t, 1H), 7.05 (d, 2H), 7.02 (d, 1H), 6.91 (d, 2H), 6.80 (dd,1H), 6.51 (d, 1H), 6.37 (d, 1H), 5.87 (s, 2H), 3.85 (dd, 2H), 3.71 (s,3H), 3.28 (m, 4H), 3.16 (bs,2H), 2.78 (bs, 2H), 2.57 (bs, 2H), 2.29-2.14(m, 6H), 1.97 (bs, 2H), 1.89 (m, 1H), 1.62 (dd, 2H), 1.40 (t, 2H), 1.26(m, 2H), 0.93 (s, 6H).

EXAMPLE 3432-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.04-10.47 (m, 1H), 9.19 (s, 1H), 8.50 (d, 1H),7.90-7.83 (m, 1H), 7.70 (d, 1H), 7.64 (s, 1H), 7.47 (d, 1H), 7.33 (dd,3H), 7.06 (d, 2H), 6.63 (d, 1H), 6.20 (d, 1H), 6.07 (s, 2H), 3.08 (s,4H), 2.95 (s, 4H), 2.75 (s, 3H), 2.42 (s, 4H), 2.19 (m, 8H), 1.97 (s,2H), 1.41 (d, 2H), 0.94 (s, 6H).

EXAMPLE 3442-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 285A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.54-11.15 (m, 1H), 8.35 (t, 2H), 8.05 (dd,1H), 7.75 (d, 1H), 7.45 (d, 1H), 7.30 (m, 2H), 7.20 (d, 1H), 7.05 (d,2H), 6.62 (d, 1H), 6.21-6.15 (m, 3H), 3.85-3.75 (m, 3H), 3.51 (m, 6H),3.12 (m, 4H), 2.79 (s, 2H), 2.21 (m, 6H), 1.97 (s, 2H), 1.40 (t, 2H),0.94 (s, 6H).

EXAMPLE 345Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 345A (4-methoxycyclohexyl)methanamine

(4-Methoxyphenyl)methanamine (1 g) in ethanol (10 mL) was treated with5% Rh-Al₂O₃ (99.8 mg) under a H₂ atmosphere (500 psi) at 50° C. for 16hours. Additional 5% Rh-Al₂O₃ (0.4 g) was added. The resulting mixturewas stirred under H₂ atmosphere (500 psi 1 at 60° C. for 2 hours. Theinsoluble material was filtered off and the filtrate was concentrated toprovide a mixture of cis and trans product as an oil, which was used fornext step without further purification.

EXAMPLE 345B4-((trans-4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide

4-Fluoro-3-nitrobenzenesulfonamide (1.098 g) and EXAMPLE 345A (1 g) intetrahydrofuran (20 mL) were treated with diisopropylethylamine (0.871mL) overnight. The reaction mixtur ewas concentrated and the residuewaspurified by reverse phase chromatography, and was eluted with 40-55%acetonitrile in 0.1% trifluoroacetic acid in water over 25 minutes toprovide the title compound.

EXAMPLE 345CTrans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared as described in EXAMPLE 110F byreplacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 318E and EXAMPLE345B, respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 8.62 (t,1H), 8.58 (d, 1H), 7.86 (dd, 1H), 7.75 (d, 1H), 7.44 (d, 1H), 7.40 (d,1H), 7.36 (d, 2H), 7.18 (d, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.18 (s,3H), 3.26-3.33 (m, 4H), 3.22 (s, 3H), 3.12 (s, 4H), 3.03-3.09 (m, 1H),2.79 (s, 2H), 2.24 (s, 4H), 2.17 (s, 2H), 1.93-2.03 (m, 4H), 1.80 (d,2H), 1.62 (dd, 1H), 1.40 (t, 2H), 0.98-1.14 (m, 4H), 0.94 (s, 6H).

EXAMPLE 3462-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 291A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.54-11.15 (m, 1H), 8.59 (t, 2H), 7.87 (dd,1H), 7.74 (d, 1H), 7.44 (d, 1H), 734 (s, 3), 7.20 (d, 1H), 7.06 (d, 2H),6.65 (dd, 1H), 6.21-6.15 (m, 3H), 3.84-3.75 (m, 3H), 3.51 (m, 6H), 3.12(s, 4H), 2.79 (s, 2H), 2.21 (d, 6H), 1.97 (s, 2H), 1.40 (t, 2H), 0.94(s, 6H).

EXAMPLE 3472-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideEXAMPLE 347A4-(3-morpholinopropylamino-3-(trifluoromethylsulfonyl)benzenesulfonamide

3-Morpholinopropan-1-amine (376 mg), EXAMPLE 131C (800 mg) andN-ethyl-N-isopropylpropan-2-amine (1.4 mL) in tetrahydrofuran (15 mL)were heated at 55° C. for 3 hours. The solvent was removed and theresidue was dissolved in ethyl acetate and washed with water and brine.The organic layer was dried over Na₂SO₄, filtered, and concentrated togive the title compound.

EXAMPLE 347B2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 347A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.31-10.55 (m, 1H), 8.14 (s, 1H), 7.96 (d, 1H),7.73 (d, 1H), 7.44 (d, 1H), 7.36 (d, 4H), 7.12 (d, 1H), 7.06 (d, 2H),6.64 (d, 1H), 6.17 (d, 3H), 3.61 (s, 4H), 3.42 (d, 2H), 3.10 (s, 4H),2.77 (s, 2H), 2.48-2.41 (m, 4H), 2.23 (s, 8H), 1.97 (s, 2H), 1.76 (s,2H), 1.40 (s, 2H), 0.94 (s, 6H).

EXAMPLE 3482-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideEXAMPLE 348A4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-(trifluoromethylsulfonyl)benzenesulfonamide

To a solution of EXAMPLE 296C (0.500 g) in tetrahydrofuran (5 mL) wasadded sodium hydride (0.596 g). Tetrahydrofuran (25 mL) was added andthe mixture was stirred for 30 minutes, and then EXAMPLE 131C (1.145 g)was added as a solution in tetrataydrofuran (5 mL). After stirring for 2hours, the reaction was partitioned between 1N aqueous HCl (50 mL) anddichloromethane (200 mL). The dichloromethane layer was dried overmagnesium sulfate, filtered, and concentrated. The resulting solid waschromatographed over silica gel (Reveleris 80 g) eluting with a gradientof 0.5% to 7.5% methanol/dichloromethane over 30 minutes (flow=40ml/min) to give the title compound.

EXAMPLE 348B2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 348A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.42 (s, 1H), 8.37-8.28 (m, 1H), 7.70 (s, 1H),7.65-7.55 (m, 1H), 7.46 (d, J=8.8, 1H), 7.37 (d, J=8.4, 3H), 7.07 (d,J=8.4, 2H), 6.67 (s, 1H), 6.23 (s, 1H), 6.12 (s, 2H), 4.47 (d, J=20.7,2H), 3.76 (s, 2H), 3.60 (s, 2H), 3.21-3.02 (m, 4H), 2.18 (s, 6H),2.01-1.79 (m, 8H), 1.42 (s, 2H), 0.95 (s, 6H).

EXAMPLE 3492-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 326A for EXAMPLE1G and EXAMPLE 318E for EXAMPLE 110E in EXAMPLE 110F, ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.53 (s, 1H), 8.22 (s, 1H), 7.72 (s, 1H),7.34-7.38 (m, 13H), 7.07 (d, 2H), 6.66 (dd, 1H), 6.23 (s, 1H), 6.12 (s,2H), 4.55 (d, 2H), 3.756-3.79 (m, 2H), 3.57-3.62 (m, 2H), 3.15 (br s,4H), 2.18 (m, 2H), 1.99 (s, 2H), 1.82-1.91 (m, 4H), 1.42 (t, 2H), 0.95(s, 6H).

EXAMPLE 3502-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 350A methyl 2-(6-amino-5-bromopyridin-3-yloxy)-4-fluorobenzoate

A mixture of example 318B (1.6 g) in N,N-dimethylformamide (50 mL) wascooled to 0° C., followed by the addition of n-bromosuccinimide (1.195g) in N,N-dimethylformamide (10 ml) solution. The reaction mixture wasstirred at 0° C. for 1 hour, and quenched with ice-cold saturated NaHCO₃aqueous solution. The reaction mixture was extracted with ethyl acetate.The combined organic phase was washed with water and brine, dried overanhydrous sodium sulfate, filtered and concentrated. The crude materialwas purified using flash column purification with 30-40% ethylacetate/hexane to provide the title compound.

EXAMPLE 350B

Methyl2-(6-amino-5-bromopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting example 350A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 350C2-(6-Amino-5-bmmopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 350B for EXAMPLE38G in EXAMPLE 38H.

EXAMPLE 350D2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 350C for EXAMPLE110E in EXAMPLE 110F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 8.52 (m,2H), 7.79 (dd, 1H), 7.73 (d, 1H), 7.49 (d, 1H), 7.40 (s, LH), 736 (d,2H), 7.13 (d, 1H), 7.06 (d, 2H), 6.64 (dd, 1H), 6.23 (d, 1H), 5.98 (s,2H), 3.85 (dd, 2H), 3.27 (m, 4H), 3.08 (s, 4H), 2.75 (s, 2H), 2.19 (m,6H), 1.93 (m, 4H), 1.63 (m, 2H), 1.40 (t, 2H), 1.27 (m, 2H), 0.94 (s,6H).

EXAMPLE 3512-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)nicotinamideEXAMPLE 351A Methyl 2-(6-amino-5-cyanopyridin-3-yloxy)-4-fluorobenzoate

EXAMPLE 350A 150 mg), zinc cyanide (28 mg) andtetrakis(triphenylphosphine)palladium(0) (61 mg) were dissolved inN,N-dimethylformamide (0.5 mL), flushed with N₂three times. The reactionmixture was heated at 120° C. for 2 hours. The reaction mixture wascooled to room temperature and diluted with ethyl acetate. The organicphase was washed with water and brine, dried over anhydrous sodiumsulfate, filtered, and concentrated. The crude material was purified bycolumn chromatogrpahy on silica gel with 2.5-5% methanol/dichloromethaneto provide the title compound.

EXAMPLE 351B Methyl2-(6-amino-5-cyanopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 351A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 351C2-(6-Amino-5-carbamoylpyridin-3-yloxy)-(4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 351B for EXAMPLE38G in EXAMPLE 38H.

EXAMPLE 351D2-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)nicotinamide

The title compound was prepared by substituting EXAMPLE 351C for EXAMPLE110E in EXAMPLE 110F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 8.50 (m,2H), 7.91 (m, 1H), 7.79 (m, 3H), 7.50 (d, 1H), 7.36 (d, 2H), 7.31 (m,1H), 7.07 (m, 5H), 6.59 (dd, 1H), 6.16 (s, 1H), 3.84 (dd, 2H), 3.27 (m,4H), 3.05 (s, 4H), 2.74 (s, 2H), 2.19 (m, 6H), 1.98 (m, 3H), 1.90 (m,1H), 1.63 (m, 2H), 1.39 (m, 2H), 1.26 (m, 2H), 0.94 (s, 6H).

EXAMPLE 3522-amino-[(6-amino-5-cyanopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 352A2-(6-Amino-5-cyanopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1

The title compound was prepared by substituting EXAMPLE 351B for EXAMPLE38G in EXAMPLE 38H.

EXAMPLE 352B2-amino-[(6-amino-5-cyanopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 352A for EXAMPLE110E in EXAMPLE 110F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 8.46 (m,2H), 7.93 (d, 1H), 7.76 (d, 1H), 7.52 (d, 1H), 7.36 (m, 3H), 7.08 (m,3H), 6.65 (dd, 1H), 6.59 (s, 2H), 6.28 (d, 1H), 3.85 (dd, 2H), 3.27 (m,4H), 3.09 (s, 4H), 2.76 (s, 2H), 2.20 (m, 6H), 1.93 (m, 5H), 1.64 (m,2H), 1.40 (t, 2H), 1.27 (m, 2H), 0.94 (s, 6H).

EXAMPLE 3532-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 353A (R)-tert-butyl1-(2,2-difluoroethyl)pyrrolidin-3-ylcarbamate

(R)-tert-butyl pyrrolidin-3-ylcarbamate (500 mg) was combined with1,1-difluoro-2-iodoethane (618 mg) and N-ethyl-N-isopropylpropan-2-amine(1.4 mL) in N,N-dimethylformamide (6 mL) in a 20 mL vial. The reactionwas heated to 70° C. for 48 hours. The reaction mixture was concentratedand the residue was purified by flash chromatography, eluting with agradient of 0-5% methanol in dichloromethane to provide the titlecompound.

EXAMPLE 353B (R)-1-(2,2-difluoroethyl)pyrrolidin-3-amine

The title compound was prepared by substituting EXAMPLE 353A for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 353C(R)-4-(1-(2,2-difluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 353B for3-(N-morpholinyl)-1-propylamine in EXAMPLE 4A.

EXAMPLE 353D2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 353C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.58 (d, 1H), 8.41 (d, 1H), 7.89 (dd, 1H), 7.73(d, 1H), 7.43 (d, 1H), 7.36 (m, 3H), 7.18 (d, 1H), 7.06 (d, 2H), 6.65(dd, 1H), 6.27, 6.13, 5.99 (each t, total 1H), 6.18 (d, 1H), 6.17 (br s,2H), 4.31 (m, 1H), 3.12 (m, 4H), 2.92 (m, 5H), 2.80 (m, 3H), 2.55 (m,1H), 2.25 (m, 4H), 2.17 (m, 2H), 1.97 (s, 2H), 1.74 (m, 1H), 1.40 (t,2H), 0.94 (s, 6H).

EXAMPLE 3542-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 131D for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.07 (d, 1H), 7.90 (dd, 1H), 7.63 (d, 1H), 7.50(d, 1H), 7.35 (d, 2H), 7.16 (s, 1H), 7.07 (m, 3H), 7.63 (dd, 1H), 6.54(br s, 1H), 6.26 (d, 1H), 5.95 (br s, 2H), 3.78 (m, 1H), 3.19 (m, 2H),3.06 (m, 5H), 2.86 (m, 2H), 2.76 (m, 2H), 2.63 (m, 2H), 2.23 (m, 4H),2.18 (m, 2H), 2.07 (m, 2H), 1.97 (s, 2H), 1.63 (m, 2H), 1.40 (t, 2H),0.94 (s, 6H).

EXAMPLE 3552-{[6-(acetylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 355A methyl2-(6-aminopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 318B for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 355B methyl2-(6-acctamidopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

EXAMPLE 355A (200 mg) was dissolved in anhydrous tetrahydrofuran (15mL), followed by addition of triethylamine (0.15 mL) and acetylchloride(0.3 mL). The reaction mixture was stirred at room temperatureovernight. The solvent was removed under vacuum. The residue waspurified by flash column purification with 20-40% ethyl acetate/hexaneto provide the title compound.

EXAMPLE 355C2-(6-acetamidopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by susbtituting EXAMPLE 355B for EXAMPLE38G in EXAMPLE 38H.

EXAMPLE 355D2-{[6-(acetylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 355C for EXAMPLE110E in EXAMPLE 110F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 10.36 (s,1H), 8.39 (m, 2H), 7.92 (d, 1H), 7.83 (s, 1H), 7.64 (m, 1H), 7.57 (d,1H), 7.36 (d, 2H), 7.15 (m, 1H), 7.07 (d, 2H), 6.98 (d, 1H), 6.68 (dd,1H), 6.34 (d, 1H), 3.85 (dd, 2H), 3.27 (m, 4H), 3.08 (s, 4H), 2.76 (s,2H), 2.20 (m, 6H), 2.06 (s, 3H), 1.99 (m, 3H), 1.89 (m, 1H), 1.62 (m,2H), 1.40 (t, 2H), 1.26 (m, 2H), 0.94 (s, 6H)

EXAMPLE 3564-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 356A methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-(methylsulfonamido)pyridin-3-yloxy)benzoate

The title compound was prepared by substituting methanesulfonyl chloridefor acetyl chloride in EXAMPLE 355B.

EXAMPLE 356B4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-(methylsulfonamido)pyridin-3-yloxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 356A for EXAMPLE38G is EXAMPLE 38H.

EXAMPLE 356C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 356B for EXAMPLE110E in EXAMPLE 110F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 10.30 (s,1H), 8.41 (s, 2H), 7.83 (s, 1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.36 (d,2H), 7.16 (d, 1H), 7.05 (m, 3H), 6.88 (d, 1H), 6.69 (dd, 1H), 6.35 (d,1H), 3.84 (dd, 2H), 3.27 (m, 7H), 3.09 (s, 4H), 2.76 (s, 2H), 2.20 (m,6H), 1.98 (m, 3H), 1.90 (m, 1H), 1.63 (m, 2H), 1.40 (t, 2H), 1.26 (m,2H), 0.95 (s, 6H).

EXAMPLE 3574-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamideEXAMPLE 357A (R)-1(1,3-difluoropropan-2-yl)pyrrolidin-3-amine

To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.500 g) and1,3-difluoropropan-2-one (0.278 g) in dichloromethane (5 mL) was addedsodium triacetoxyborohydride (0.853 g). After stirring for 1 hour, thereaction was quenched with saturated NaHCO₃solution (5 mL). The productwas extracted into dichloromethane (25 mL), dried over magnesiumsulfate, filtered, and concentrated. The resulting crude material wastreated with HCl (4.0 M in dioxane, 4 mL) and methanol (1 mL) andstirred for 1 hour. The mixture was concentrated to provide the titlecompound.

EXAMPLE 357B(R)-4-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

To 4-fluoro-3-nitrobenzenesulfonamide (0.272 g) and(R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-amine (0.195 g) intetrahydrofuran (3.0 mL) was added N-ethyl-N-isopropylpropan-2-amine(0.512 mL) and the reaction was stirredat room temperature. Afterstirring for 6 hours, the reaction was concentrated, loaded onto silicagel (Reverleris 40 g) and the product was purified by flashchromatography using a gradient of 25% to 100% ethyl acetate/hexanesover 30 minutes to provide the title compound.

EXAMPLE 357C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 154E for EXAMPLE1F and EXAMPLE 357B for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.21 (s, 2H), 8.58 (d, 1H), 8.39 (d, 1H), 7.89(d, 1H), 7.51 (d, 1H), 7.40-7.25 (m, 5H), 7.13 (d, 1H), 7.03 (d, 2H),6.67 (s, 1H), 6.40 (s, 1H), 6.09 (s, 1H), 4.62 (dd, 4H), 4.31-4.18 (m,1H), 3.04 (s, 6H), 2.73 (s, 4H), 2.39-2.23 (m, 2H), 2.19 (s, 6H), 1.95(s, 2H), 1.79-1.60 (m, 1H), 1.38 (s, 2H), 0.92 (s, 6H).

EXAMPLE 3582-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 65A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.56 (d, 1H), 8.24 (d, 1H), 7.85 (dd, 1H), 7.72(d, 1H), 7.44 (d, 1H), 7.35 (m, 3H), 7.22 (d, 1H), 7.06 (d, 2H), 6.64(dd, 1H), 6.19 (d, 1H), 6.12 (br s, 2H), 3.74 (m, 2H), 3.11 (m, 5H),2.91 (m, 2H), 2.76 (m, 3H), 2.22 (m, 6H), 1.97 (m, 4H), 1.58 (m, 2H),1.40 (t, 2H), 0.94 (s, 6H), 0.46 (m, 2H), 0.36 (m, 2H).

EXAMPLE 3592-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 350C for EXAMPLE110E and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 110F. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.96 (s, 1H), 8.41 (d, 1H), 7.77 (dd, 1H), 7.67(d, 1H), 7.53 (dd, 2H), 7.36 (d, 2H), 7.29 (d, 1H), 7.07 (d, 2H), 6.62(dd, 1H), 6.26 (d, 1H), 5.85 (s, 2H), 3.28 (m, 4H), 3.06 (s, 4H), 2.90(m, 4H), 2.75 (s, 2H), 2.31 (s, 3H), 2.20 (m, 7H), 1.97 (s, 2H), 1.40(t, 2H), 0.94 (s, 6H).

EXAMPLE 3602-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 350C for EXAMPLE110E and EXAMPLE 296D for EXAMPLE 1G in EXAMPLE 110F. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.19 (d, 1H), 7.85 (dd, 1H), 7.62 (d, 1H), 7.57(d, 1H), 7.36 (d, 2H), 7.31 (d, 1H), 7.22 (d, 1H), 7.08 (d, 2H), 6.63(dd, 1H), 6.30 (d, 1H), 5.81 (s, 2H), 4.34 (d, 2H), 3.78 (m, 2H), 3.59(m, 2H), 3.06 (s, 4H), 2.76 (s, 2H), 2.21 (m, 6H), 1.97 (s, 2H), 1.86(m, 4H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 3612-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 350C for EXAMPLE110E and EXAMPLE 291A for EXAMPLE 1G in EXAMPLE 110F. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.48 (m, 2H), 7.78 (m, 1H), 7.68 (m, 1H), 7.50(m, 1H), 7.35 (m, 3H), 7.06 (m, 3H), 6.62 (m, 1H), 6.25 (m, 1H), 5.92(m, 2H), 3.79 (m, 3H), 3.63 (m, 2H), 3.49 (m, 2H), 3.40 (m, 3H), 3.08(s, 4H), 2.76 (s, 2H), 2.19 (m, 6H), 1.97 (s, 2H), 1.40 (t, 2H), 0.94(s, 6H).

EXAMPLE 3622-[(6-amino-5-methylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 362A methyl 2-(6-amino-5-methylpyridin-3-yloxy)-4-fluorobenzoate

EXAMPLE 350A (260 mg),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (25 mg), andpalladium(II) acetate (7 mg) were suspended in anhydrous tetrahydrofuran(2 mL). The mixture was flushed with N₂ three times and stirred at roomtemperature for 5 minutes followed by addition of methylzinc(II)chloride (0.45 mL). The reaction mixture was stirred at room temperaturefor 3 hours. The reaction was quenched with saturated NH₄Cl aqueoussolution and diluted with ethyl acetate. The organic phase was washedwith water and brine, dried over anhydrous sodium sulfate, filtered andeconcentrated. The residue was purified by flash column purification with60-100% ethyl acetate/hexane to provide the title compound.

EXAMPLE 362B methyl2-(6-amino-5-methylpyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 362A for EXAMPLE3A in EXAMPLE 3G.

EXAMPLE 362C2-(6-amino-5-methylpyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 362B for EXAMPLEG in EXAMPLE 38 H.

EXAMPLE 362D2-[(6-amino-5-methylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 362C for EXAMPLE110E in EXAMPLE 110F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 8.57 (m,2H), 7.86 (dd, 1H), 7.58 (d, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.19 (d,1H), 7.05 (m, 3H), 6.60 (dd, 1H), 6.10 (d, 1H), 5.61 (s, 2H), 3.85 (dd,2H), 3.25 (m, 4H), 3.05 (s, 4H), 2.74 (s, 2H), 2.18 (m, 6H), 1.97 (m,7H), 1.63 (m, 2H), 1.39 (t, 2H), 1.25 (m, 2H), 0.94 (s, 6H).

EXAMPLE 3632-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 337D for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.53-11.08 (m, 1H), 8.66 (t, 1H), 8.59 (d, 1H),7.87 (dd, 1H), 7.75 (d, 1H), 7.38 (ddd, 5H), 7.06 (d, 2H), 6.65 (dd,1H), 6.18 (s, 3H), 3.77 (dd, 4H), 3.52 (dd, 2H), 3.12 (s, 4H), 2.81 (s,2H), 2.22 (d, 6H), 2.03-1.67 (m, 6H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 3642-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamideEXAMPLE 364A tert-butyl 1-(oxetan-3-yl)piperidin-4-ylcarbamate

The title compound was prepared by substitutingtert-butylpiperidin-4-ylcarbamate for tert-butylpiperazine-1-carboxylate and oxetan-3-one for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

EXAMPLE 364B 1-(oxetan-3-yl)piperidin-4-amine

The title compound was prepared by substituting EXAMPLE 364A for EXAMPLE251A is EXAMPLE 1B.

EXAMPLE 364C3-nitro-4-(1-(oxetan-3-yl)piperidin-4-ylamino)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 364B for1-isopropylpiperidinyl-4-amine in EXAMPLE 41A.

EXAMPLE 364D2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 364C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.57 (d, 1H), 8.28 (d, 1H), 7.86 (dd, 1H), 7.73(d, 1H), 7.43 (d, 1H), 7.36 (m, 3H), 7.23 (d, 1H), 7.06 (d, 2H), 6.64(dd, 1H), 6.17 (m, 3H), 4.55 (t, 2H), 4.44 (t, 2H), 3.76 (br s, 1H),3.46 (br s, 1H), 3.11 (m, 5H), 2.77 (m, 2H), 2.67 (m, 2H), 2.20 (m, 6H),2.08 (m, 1H), 1.97 (m, 4H), 1.65 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 3652-[(6-amino-5-isopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 365A methyl2-(6-amino-5-isopropylpyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 350B for EXAMPLE350A and isopropylzinc(II) chloride for methylzinc(II) chloride inEXAMPLE 362A.

EXAMPLE 365B2-(6-amino-5-isopropylpyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 365A for EXAMPLE380 in EXAMPLE 38H.

EXAMPLE 365C2-[(6-amino-5-isopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 365B for EXAMPLE110E in EXAMPLE 110F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 8.61 (m,2H), 7.88 (m, 1H), 7.61 (dd, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.22 (dd,1H), 7.07 (m, 3H), 6.60 (dd, 1H), 6.06 (dd, 1H), 5.71 (d, 2H), 3.85 (dd,1H), 3.27 (m, 4H), 3.06 (s, 4H), 2.90 (m, 1H), 2.74 (s, 2H), 2.38 (t,1H), 2.17 (m, 6H), 1.92 (m, 3H), 1.63 (m, 2H), 1.52 (m, 1H), 1.39 (t,2H), 1.26 (m, 2H), 1.11 (d, 6H), 0.93 (s, 6H).

EXAMPLE 3662-[(6-amino-5-cyclopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 366A methyl2-(6-smino-5-cyclopropylpyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 350B for EXAMPLE350A and cyclopropylzinc(II) chloride for methylzinc(II) chloride inEXAMPLE 362A.

EXAMPLE 366B2-(6-amino-5-cyclopropylpyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 366A for EXAMPLE38G in EXAMPLE 38H.

EXAMPLE 366C2-[(6-amino-5-cyclopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 366B for EXAMPLE110E in EXAMPLE 110F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 8.64 (t,1H), 8.59 (d, 1H), 7.88 (dd, 1H), 7.60 (d, 1H), 7.45 (d, 1H), 7.35 (d,2H), 7.23 (d, 1H), 7.06 (d, 2H), 6.91 (d, 1H), 6.61 (dd, 1H), 6.04 (d,1H), 5.83 (s, 2H), 3.85 (dd, 2H), 3.27 (m, 4H), 3.06 (s, 4H), 2.73 (s,2H), 2.18 (m, 6H), 1.97 (m, 3H), 1.65 (m, 3H), 1.40 (t, 2H), 1.26 (m,2H), 0.94 (s, 6H), 0.87 (m, 2H), 0.49 (m, 2H).

EXAMPLE 367Trans-2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 350C for EXAMPLE110E and EXAMPLE 345B for EXAMPLE 1G in EXAMPLE 110F. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.50 (m, 2H), 7.78 (d, 1H), 7.73 (d, 1H), 7.48(d, 1H), 7.40 (s, 1H), 7.36 (d, 2H), 7.07 (m, 3H), 6.64 (dd, 1H), 6.22(s, 1H), 5.98 (s, 2H), 3.27 (m, 4H), 3.22 (s, 3H), 3.06 (m, 4H), 2.76(s, 2H), 2.20 (m, 6H), 1.99 (m, 4H), 1.80 (d, 2H), 1.62 (s, 1H), 1.40(t, 2H), 1.04 (m, 4H), 0.94 (s, 6H).

EXAMPLE 3684-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 368A methyl 4-fluoro-3-(3-fluoro-2-nitrophenoxy)benzoate

To a solution of methyl 4-fluoro-2-hydroxybenzoate (1.225 g) inanhydrous tetrahydrofuran (25 mL) was added potassium t-butoxide (0.808g). The mixture was stirred for 20 minutes at room temperature. Asolution of 1,3-difluoro-2-nitrobenzene (0.955 g) in tetrahydrofuran (6mL) was then added dropwise. The resulting mixture was stirred at roomtemperature for 1 hour, then at 80° C. overnight. The reaction mixturewas quenched with water (40 mL) and extracted with dichlorormethane. Theorganic solution was dried (MgSO₄), filtered and concentrated. Theresidue was purified on a silica gel column, eluting with 25% ethylacetate in hexane to obtain the title compound.

EXAMPLE 368B methyl2-(3-(bis-(4-methoxyphenyl)methylamino)-2-nitrophenoxy)-4-fluorobenzoate

A solution of EXAMPLE 368A (1.33 g), bis(4-methoxyphenyl)methanamine(1.046 g) and N-ethyl-N-isopropylpropan-2-amine (1.127 ml) in anhydrous1-methyl-2-pyrrolidinone (20 mL) was stirred at 120° C. overnight. Themixture was concentrated and the residue was taken up in water (100 mL)and extracted with dichloromethane. The residue was absorbed on silicaand purified by chromatography on a silica gel column, duringwith 25%ethyl acetate in hexane to provide the title compound.

EXAMPLE 368C methyl2-(2-amino-3-(bis(4-methoxyphenyl)methylamino)phenoxy)-4-fluorobenzoate

A solution of EXAMPLE 368B (1.1 g) in methanol was hydrogenated overRaney Ni, at 60 psi of H₂ at room temperature. the filtered solution wasconcentrated to give the title compound.

EXAMPLE 368D methyl2-(1-(bis(4-methoxyphenyl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yloxy)-4-fluorobenzoate

A solution of EXAMPLE 368C (0.58 g) andN-ethyl-N-isopropylpropan-2-amine (0.804 ml) in dichloromethane (8 mL)was cooled with an ice bath. Then, a 20 wt % solution of phosgene intoluene (0.850 ml) was added dropwise. The mixture was stirred at roomtemperature overnight. The mixture was diluted with dichloromethane andwashed with 5% aq. NaHCO₃. The material was then absorbed on silica andpurified on a silica gel column eluting with 50% ethyl acetate in hexaneto provide the title compound.

EXAMPLE 368E methyl2-(1-(bis(4-methoxyphenyl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yloxy)-4-fluorobenzoate

To a solution of EXAMPLE 368D (250 mg) in anhydrousN,N-dimethylformamide (6 mL) was added sodium hydride (34.1 mg). Themixture was stirred at 50° C. for 30 minutes. Then, iodomethane (35.6μl) was added and the mixture was stirred at 5° C. overnight. Thereaction mixture was quenched with water (30 mL), then extracted withethyl acetate. The solution was dried (MgSO₄), filtered and concentratedto give the title compound.

EXAMPLE 368F methyl2-(1-(bis(4-methoxyphenyl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yloxy)-4-(piperazin-1-yl)benzoate

A flask was charged with EXAMPLE 368E (281 mg), anhydrousN,N-dimethylformamide (6 mL) and piperazine (268 mg). The mixture wasstirred at 75° C. overnight. The solvent was evaporated and the residuewas re-dissolved in ethyl acetate. The crude product was purified on asilica gel column eluting with 5% methanol in dichloromethane to providethe title compound.

EXAMPLE 368G methyl2-(1-(bis(4-methoxyphenyl)methyl)-3-methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

To a solution of EXAMPLE 368F (273 mg)and EXAMPLE 60D (169 mg) inanhydrous dichloromethane (5 mL) was added sodium triacetoxxyborohydride(172 mg) in several portions over 5 minutes. The resulting mixture wasstirred at ambient temperature overnight. The mixture was quenched with5% aqueous Na₂CO₃ solution (10 mL) and extracted with dichloromethane.The crude product was purified on a silica gel column eluted with 45%ethyl acetate in hexane to provide the title compound.

EXAMPLE 368H2-(1-(bis(4-methoxyphenyl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 368G for EXAMPLE 38Gin EXAMPLE 38H.

EXAMPLE 368I2-(1-(bis(4-methoxyphenyl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

This example was prepared by substituting by substituting EXAMPLE 368Hfor EXAMPLE 1F in EXAMPLE 1H.

EXAMPLE 368J4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

A solution of EXAMPLE 368I (140 mg) in dichloromethane (10 mL) wascooled with an ice bath. Trifluoroacetic acid (10 mL) was added. Theresulting solution was allowed to warm to room temperature and stirredfor 48 hours. The solution was concentrated and the residue wastriturated with diethyl ether. The resulting solid was purified byreverse-phase HPLC using a Waters Preparative LC4000 system wtihPhenomenex Luna C18 column and a water-acetonitrile mobile phasebuffered with ammonium acetate to proivde the title compound. ¹H NMR(500 MHz, pyridine-d₅) δ 12.34 (s, 1H), 9.20 (d, 1H), 8.87 (t, 1H), 8.44(dd, 1H), 8.01 (d, 1H), 7.44 (d, 2H), 7.08 (d, 2H), 7.01 (d, 1H),6.86-6.79 (m, 3H), 6.74 (d, 1H), 6.52 (dd, 1H), 3.96 (dd, 2H), 3.65 (s,3H), 3.30 (d, 2H), 3.24 (m, 2H), 3.19 (m, 4H), 2.81 (s, 2H), 2.30-2.28(m, 2H), 2.23 (m, 4H), 1.97 (s, 2H), 1.85-1.75 (m, 1H), 1.58 (d, 2H),1.40 (t, 2H), 1.33 (dq, 2H), 0.94 (s, 6H).

EXAMPLE 3692-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 369A tert-butyl2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting tert-butyl2-aminomethyl)morpholine-4-carboxylate for3-(N-morpholinyl)-1-propylamine in EXAMPLE 4A.

EXAMPLE 369B 4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide

A solution of EXAMPLE 369A (0.8 g) in methylene chloride (10 mL) andtrifluoroacetic acid (10 mL) was stirred at room temperature for 2hours. The solvents were evaporated and the residue was triturated withdiethyl ether. The resulting solid was dissolved in 5% aqueous sodiumcarbonate solution (20 mL). The mixture was concentrated to dryness andthe resulting soid was triturated with a solution of 10% methanol inmethylene chloride several times. Evaporation of the organic solventprovided the title compound.

EXAMPLE 369C4-((4-cyclopropylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

A solution of EXAMPLE 369B (0.633 g) and(1-ethyoxycyclopropoxy)trimethylsilane (1.601 mL) in anhydrous methanol(15 mL) and acetic acid (1.717 mL) was refluxed for 30 minutes andallowed to cool to room temperature. Sodium cyanoborohydride (0.377 g)was then added and the mixture was stirred at ambient temperatureovernight. The reaction mixture was concentrated to dryness. The residuewas mixed with 5% aqueous Na₂CO₃ solution (25 mL) and extracted withethyl acetate. The crude product was purified on a silica gel columneluting with 5% to 10% methanol in dichloromethane to provide the titlecompound.

EXAMPLE 369D2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 369C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.34 (br s, 1H), 8.63 (t, 1H), 8.58 (d, 1H),7.86 (dd, 1H), 7.73 (d, 1H), 7.45 (d, 1H), 7.38 (d, 1H), 7.36 (d, 2H),7.20 (d, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.19 (d, 1H), 6.17 (br s,2H), 3.83 (m, 1H), 3.64 (m, 1H), 3.56 (m, 1H), 3.45 (m, 2H), 3.12 (m,4H), 2.91 (m, 1H), 2.74 (m, 3H), 2.26 (m, 5H), 2.15 (m, 3H), 1.97 (m,2H), 1.66 (m, 1H), 1.40 (t, 2H), 0.94 (s, 6H), 0.42 (m, 2H), 0.33 (m,2H).

EXAMPLE 3702-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 370A (R)-tert-butyl 1-cyclopropylpyrrolidin-3-ylcarbamate

The title compound was prepared by substituting (R)-tert-butylpyrrolidine-3-ylcarbamate for tert-butyl(trans)-4-aminocyclohexylcarbamate in EXAMPLE 334A.

EXAMPLE 370B (R)-1-cyclopropylpyrrolidin-3-amine

The title compound was prepared by substituting EXAMPLE 370A for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 370C(R)-4-(1-cyclopropylpyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 370B for1-isopropylpiperidinyl-4-amine in EXAMPLE 41A.

EXAMPLE 370D2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 370C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.52 (d, 1H), 8.33 (d, 1H), 7.84 (dd, 1H), 7.69(d, 1H), 7.46 (d, 1H), 7.36 (m, 2H), 7.30 (d, 1H), 7.10 (d, 1H), 7.06(d, 2H), 6.64 (dd, 1H), 6.21 (d, 1H), 6.09 (br s, 2H), 4.27 (m, 1H),3.09 (m, 4H), 3.01 (m, 1H), 2.91 (m, 1H), 2.76 (m, 3H), 2.62 (m, 1H),2.22 (m, 6H), 1.97 (m, 2H), 1.76 (m, 1H), 1.68 (m, 1H), 1.40 (t, 2H),0.94 (s, 6H), 0.43 (m, 2H), 0.37 (m, 2H).

EXAMPLE 3712-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}benzamideEXAMPLE 371A4-((1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

To a suspension of EXAMPLE 341C (0.100 g) and 1,3-difluoropropan-2-one(0.025 g) in dichloromethane (2 mL) was added sodiumtriacetoxyborohydride (0.071 g). After 15 minutes, N,N-dimethylformamideadded dropwise unitl an organe solution resulted (˜15 drops). Afterstirring overnight additional 1,3-difluoropropan-2-one and sodiumtriacetoxyborohydride were added. After 3 hours, the reaction was loadedonto silica gel (Reverleris 40 g) and eluted with a gradient of 0.5-5%methanol/dichloromethane over 30 minutes (flow=40 ml/minutes) to providethe title compound.

EXAMPLE 371B2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 371A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 12.05-10.74 (m, 1H), 8.38 (s, 1H), 8.08 (s, 1H),7.73 (d, 1H), 7.50 (dd, 2H), 7.37 (d, 3H), 7.07 (d, 2H), 6.65 (d, 1H),6.18 (d, 3H), 4.62 (dd, 4H), 4.38 (d, 2H), 3.16 (s, 5H), 2.97-2.60 (m,8H), 2.18 (s, 4H), 2.07-1.60 (m, 6H), 1.42 (s, 2H), 0.94 (s, 6H).

EXAMPLE 372 tert-butyl6bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenyoxy)pyridin-2-ylcarbamateEXAMPLE 372A 2-(2,6-Dibromo-pyridin-4-yloxy)-4-fluoro-benzoic acidmethyl ester

A soltuion of methyl 4-fluoro-2-hydroxybenzoate (2.00 g),2,6-dibromo-4-nitropyridine (3.65 g), and cesium carbonate (4.21 g) inN,N-dimethylformamide (100 mL) was heated to 55° C. for 16 hours,cooled, added to water, and extracted with 50% ethyl acetate in hexanes.The organic extract was washed with brine, dried over anhydrous sodiumsulfate, filtered, concentrated and purified by flash columnchromatography on silica gel using 30-50% ethyl acetate in hexanes.

EXAMPLE 372B2-(2-Bromo-6-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-fluoro-benzoicacid methyl ester

EXAMPLE 372A (1400 mg), tert-butyl carbamate (405 mg), and cesiumcarbonate (1689 mg) were added to 1,4-dioxane (24 mL). The solution wasdegassed and flushed with nitrogen three times. Palladium(II) acetate(39 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (200 mg)were added, and the solution was heated at 80° C. for 2.5 hours, cooled,added to water, and extracted with 50% ethyl acetate in hexanes. Theextract was washed with brine, dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography onsilica gel using 10-20% ethyl acetate in hexanes.

EXAMPLE 372C2-(2-Bromo-6-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-piperazin-1-yl-benzoicacid methyl ester

The title compound was prepared by substituting EXAMPLE 372B for EXAMPLE342D in EXAMPLE 342E.

EXAMPLE 372D2-(2-Bromo-6-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoicacid methyl ester

The title compound was prepared by substituting EXAMPLE 60D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 372C fortert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 372E2-(2-Bromo-6-tert-butyoxycarbonylamino-pyridin-4-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoicacid

The title compound was prepared by substituting EXAMPLE 372D for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 372F tert-butyl6-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate

The title compound was prepared by substituting EXAMPLE 372E for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 9.93 (s, 1H),8.58 (bs, 1H), 8.47 (d, 1H), 7.70 (d, 1H), 7.57 (d, 1H), 7.37 (d, 2H),7.18 (d, 1H), 7.08 (d, 1H), 7.07 (d, 2H), 6.83 (dd, 1H), 6.63 (bs, 1H),6.40 (d, 1H), 3.87 (dd, 2H), 3.35-3.25 (m, 8H), 2.85 (bs, 2H), 2.40-2.15(m, 6H), 1.97 (bs, 2H), 1.93 (m, 1H), 1.65 (d, 2H), 1.41 (t, 2H), 1.40(s, 9H), 1.36-1.22 (m, 2H), 0.95 (s, 6H).

EXAMPLE 3734-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 373A2-(2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-fluoro-benzoicacid methyl ester

The title compound was prepared during the synthesis of EXAMPLE 372B.

EXAMPLE 373B2-(2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-piperzin-1-yl-benzoicacid methyl ester

The title compound was prepared by substituting EXAMPLE 373A for EXAMPLE342D in EXAMPLE 342E.

EXAMPLE 373C2-(2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]piperazin-1-yl}-benzoicacid methyl ester

The title compound was prepared by substituting EXAMPLE 60D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 373B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 373D

2-(2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoicacid

The title compound was prepared by substituting EXAMPLE 373C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 373E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 373D for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 9.12 (bs,2H), 8.57 (m, 1H), 8.50 (d, 1H), 7.72 (dd, 1H), 7.53 (d, 1H), 7.36 (d,2H), 7.12 (d, 1H), 7.06 (d, 2H), 6.86 (s, 2H), 6.79 (dd, 1H), 6.56 (bs,1H), 3.86 (dd, 2H), 3.27-3.18 (m, 8H), 2.79 (bs, 2H), 2.31-2.15 (m, 6H),1.97 (bs, 2H), 1.93 (m, 1H), 1.64 (d, 2H), 1.42 (t, 2H), 1.41 (s, 18H),1.33-1.23 (m, 2H), 0.94 (s, 6H).

EXAMPLE 3744-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[6-(cyclopropylamino)pyridin-3-yl]oxy}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 374A methyl2-(6-(cyclopropylamino)pyridin-3-yloxy)-4-fluorobenzoate

The title compound was prepared by substituting cyclopropyl amine fortert-butyl carbamate in EXAMPLE 377B.

EXAMPLE 374B methyl2-(6-(cyclopropylamino)pyridin-3-yloxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 374A for EXAMPLE377E in EXAMPLE 377F.

EXAMPLE 374C methyl4-(4-((2-(4-chlorophenyl)-4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-(cyclopropylamino)pyridin-3-yloxy)benzoate

The title compound was prepared by substituting EXAMPLE 374B fortert-butyl piperazine-1-carboxylate and EXAMPLE 60D for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

EXAMPLE 374D4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-(cyclopropylamino)pyridin-3-yloxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 374C for EXAMPLE38G in EXAMPLE 38H.

EXAMPLE 374E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[6(cyclopropylamino)pyridin-3-yl]oxy}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 374D for EXAMPLE110E in EXAMPLE 110F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 8.54 (m,2H), 7.85 (m, 1H), 7.77 (d, 1H), 7.48 (d, 1H), 7.36 (d, 2H), 7.17 (m,2H), 7.06 (d, 2H), 6.60 (m, 3H), 6.13 (d, 1H), 3.85 (dd, 2H), 3.26 (m,4H), 3.05 (s, 4H), 2.74 (s, 2H), 2.47 (m, 2H), 2.18 (m, 6H), 1.92 (m,3H), 1.61 (m, 2H), 1.40 (t, 2H), 1.27 (m, 2H), 0.94 (s, 6H), 0.68 (m,2H), 0.41 (m, 2H).

EXAMPLE 375Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-[(4-{[(4-(methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 375A methyl2-(6-(2.2-difluoroethylamino)pyridin-3-yloxy)-4-fluorobenzoate

The title compound was prepared by substituting 2,2-difluoroethananminefor tert-butyl carbamate in EXAMPLE 377B.

EXAMPLE 375B methyl2-(6-(2,2-difluoroethylamino)pyridin-3-yloxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 375A for EXAMPLE377E in EXAMPLE 377F.

EXAMPLE 375C methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-(2,2-difluoroethylamino)pyridin-3-yloxy)benzoate

The title compound was prepared by substituting EXAMPLE 375B fortert-butyl piperazine-1-carboxylate and EXAMPLE 60D for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

EXAMPLE 375D4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-(2,2-difluoroethylamino)pyridin-3-yloxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 375C for EXAMPLE38G in EXAMPLE 38H.

EXAMPLE 375ETrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-[(4-{[(4-(methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 375D for EXAMPLE110E and EXAMPLE 345B for EXAMPLE 1G in EXAMPLE 110F. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.52 (m, 2H), 7.84 (dd, 1H), 7.75 (d, 1H), 7.47(d, 1H), 7.35 (m, 2H), 7.16 (m, 2H), 7.05 (d, 2H), 6.87 (t, 1H), 6.60(m, 2H), 6.10 (m, 2H), 3.66 (m, 2H), 3.27 (m, 4H), 3.23 (s, 3H), 3.05(s, 4H), 2.74 (s, 2H), 2.18 (m, 6H), 1.99 (m, 4H), 1.79 (m, 2H), 1.61(m, 1H), 1.40 (t, 2H), 1.07 (m, 4H), 0.94 (s, 6H).

EXAMPLE 3764-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 375D for EXAMPLE110E in EXAMPLE 110F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 8.55(m,2H), 7.86 (dd, 1H), 7.76 (d, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.18 (m,2H), 7.06 (d, 2H), 6.89 (m, 1H), 6.61 (m, 2H), 6.10 (m, 2H), 3.85 (dd,2H), 3.66 (m, 2H), 3.27 (m, 4H), 3.06 (s, 4H), 2.74 (s, 2H), 2.18 (m,6H), 1.94 (m, 4H), 1.62 (d, 2H), 1.40 (t, 2H), 1.28 (m, 2H), 0.94 (s,6H).

EXAMPLE 3772-{[5-chloro-6-(methylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 377A methyl 2-(6-chloropyridin-3-yloxy)-4-fluorobenzoate

To a solution of 6-chloropyridin-3-ol (2.41 g) in2-methyltetrahydrofuran (20 mL) and N,N-dimethylformamide (4 mL) wasadded potassium tert-butoxide (1.0 M in tetrahydrofuran) (18.60 mL). Thereaction was stirred for 15 minutes, then methyl 2,4-difluorobenzoate(3.52 g) was added as a solution in 2-methyltetrahydrofuran (2 mL). Thereaction was then heated to 80° C. and stirred under a nitrogenatmosphere for 3 days. The reaction was cooled, diluted with ethylacetate (100 mL), washed with water (50 mL), 1N aqueous HCl (50 mL), andbrine (50 mL), dried over magnesium sulfate, filtered, and concentrated.Silica gel chromatography (Reveleris 80 g), eluting with 10% ethylacetate/hexanes provided the title compound.

EXAMPLE 377B methyl2-(6-(tert-butoxycarbonylamino)pyridin-3-yloxy)-4-fluorobenzoate

To EXAMPLE 377A (3.30 g), tert-butylcarbamate (1.51 g) and cesiumcarbonate (5.73 g) in dioxane (30 mL) was added diacetoxypalladium(0.079 g) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)(0.41 g) and the reaction was heated to 85° C. overnight under anatmosphere of nitrogen. The reaction was cooled, diluted with ethylacetate (100 mL) and washed with water (75 mL) and brine (75 mL) driedover magnesium sulfate, filtered, and concentrated. Silica gelchromatography (Reveleris 80 g) eluting with 10% ethyl acetate/hexanesover 20 minutes provided the title compound.

EXAMPLE 377C methyl2-(6-tert-butoxycarbonyl(methyl)amino)pyridin-3-yloxy)-4-fluorobenzoate

To a solution of EXAMPLE 377B (0.750 g) in N,N-dimethylformamide (5 mL)was added sodium hydride (0.091 g). The reaction was stirred for 30minutes at room temperature and the niodomethane(0.142 mL) was added tothe reaction and stirring was continued at room temperature for 2 hours.The reaction was quenched with water (25 mL) and extracted with ethylacetate (75 mL). The organic layer was separated, washed with brine (50mL), dried over magnesium sulfate, filtered, and concentrated. Theresidue was loaded onto silica gel (Reveleris 40 g) and eluted with agradient of 5-15% ethyl aeetate/hexanes over 30 minutes (flow=40 ml/min)to provide the title compound.

EXAMPLE 377D methyl 4-fluoro-2-(6-(methylamino)pyridin-3-yloxy)benzoate

To EXAMPLE 377C (0.714 g) in dichloromethane (10 mL) was addedtrifluoroacetic acid (1.5 mL). After stirring for 3 hours, the reactionwas concentrated, dissolved in dichloromethane (100 mL), washed withsaturated aqueous NaHCO₃ (2×75 mL) and brine (75 mL), dried overmagnesium sulfate, filtered, and concentrated to proivde the titlecompound.

EXAMPLE 377E methyl2-(5-chloro-6-methylamino)pyridin-3-yloxy)-4-fluorobenzoate

A solution of EXAMPLE 377D (0.450 g) and N-chlorosuccinimide (0.239 g)was stirred together in N,N-dimethylformamide 10 mL) at roomtemperature. The reaction was stirred for 48 hours, diluted with ethylacetate (100 mL), washed with water (2×50 mL) and brine (50 mL), driedover magnesium sulfate, filtered, and concentrated. Silica gelchromatography (Reveleris 40 g) eluting with a gradient of 5-30% ethylacetate/hexanes over 30 minutes (flow=40 ml/min) provided the titlecompound.

EXAMPLE 377F methyl2-(5-chloro-6-(methylamino)pyridin-3-yloxy)-4-(piperazin-1-yl)benzoate

A solution of EXAMPLE 377E (0.230 g) and piperazine (0.255 g) indimethylsulfoxide (3 mL) was heated to 85° C. for 1 hour. The reactionwas cooled and diluted with ethyl acetate (75 mL). The organic layer waswashed with water (3×50 mL) and brine (50 mL), dried over magnesiumsulfate, filtered, and concentrated to give the title compound.

EXAMPLE 377G methyl2-(5-chloro-6-(methylamino)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

To a solution of EXAMPLE 377F (0.230 g) and EXAMPLE 60D (0.182 g) indichloromethane (2 mL) was added sodium triacetoxyborohydride (0.194 g)and the reaction was allowed to stir at room temperature overnight. Thereaction was quenched with saturated aqueous NaHCO₃ solution (25 mL) andexracted into dichloromethane (75 mL). The organic layer was washed withbrine (25 mL), dried over magnesium sulfate, filtered, and concentrated.Silica gel chromatography (Reveleris 40 g) eluting with a gradient of5-30% ethyl acetate/hexanes over 30 minutes provided the title compound.

EXAMPLE 377 H2-(5-chloro-6-(methylamino)pyridin-3-oxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

To a solution of EXAMPLE 377G (0.295 g) in tetrahydrofuran (5 mL) andmethanol (2 mL) was added 1.0 M aqueous LiOH (1.452 mL) and the reactionwas heated to 55° C. After stirring for 3 hours, the reaction wascooled, diluted with dichloromethane (75 mL) and water (15 mL) andquenched with 1N aqueous HCl (1.45 mL). The organic layer was separated,washed with brine (15 mL), dried over magnesium sulfate, filtered, andconcentrated to provide the title compound.

EXAMPLE 377I2-{[5-chloro-6-(methylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 377 H forEXAMPLE 1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.52-11.16 (m, 1H), 8.63 (s, 1H), 8.57 (d, 1H), 7.87 (dd, 1H), 7.82 (d,1H), 7.49-7.39 (m, 2H), 7.36 (d, 2H), 7.21 (d, 1H), 7.06 (d, 2H), 6.65(d, 1H), 6.43 (d, 1H), 6.18 (d, 1H), 3.85 (d, 2H), 3.41-3.19 (m, 4H),3.12 (s, 4H), 2.84 (d, 3H), 2.79 (s, 2H), 2.20 (d, 6H), 1.97 (s, 3H),1.62 (d, 2H), 1.41 (d, 2H), 1.29 (dd, 2H), 0.94 (s, 6H).

EXAMPLE 3782-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-fluoro-1-(fluoromethyl)ethyl]morpholin-2yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamideEXAMPLE 378A tert-butyl(4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate

The title compound was prepared by substitutingtert-butylmorpholin-2-ylmethylcarbamate fortert-butylpiperazine-1-carboxylate and 1,3-difluoropropan-2-one for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A

EXAMPLE 378B (4-(1,3-difluoroprapan-2-yl)morpholin-2-yl)methanamine

The title compound was prepared by substituting EXAMPLE 378A for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 378C4-((4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 378B for3-(N-morpholinyl)-1-propylamine in EXAMPLE 4A.

EXAMPLE 378D2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-fluoro-1-(fluoromethyl)ethyl]morpholin-2yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 378C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.30 (br s, 1H), 8.63 (t, 1H), 8.58 (d, 1H),7.86 (dd, 1H), 7.74 (d, 1H), 7.44 (d, 1H), 7.38 (d, 1H), 7.36 (d, 2H),7.20 (d, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.19 (d, 1H), 6.17 (br s,2H), 4.68 (t, 2H), 4.56 (t, 2H), 3.83 (d, 1H), 3.71 (m, 1H), 3.51 (m,4H), 3.12 (m, 4H), 2.90 (d, 1H), 2.80 (m, 2H), 2.73 (m, 1H), 2.57 (t,1H), 2.42 (t, 1H), 2.25 (m, 4H), 2.17 (m, 2H), 1.97 (m, 2H), 1.40 (t,2H), 0.94 (s, 6H).

EXAMPLE 3792-[(2-amino-6-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

EXAMPLE 372F (137 mg) was dissolved in dichloromethane (2 mL), andtrifluoroacetic acid (0.21 mL) was added. The mixture was stirred atroom temperature for 16 hours, diluted with dichloromethane, extractedwith saturated aqueous sodium bicarbonate, dried over anhydrous sodiumsulfate, and concentrated under vacuum to provide the title compound. ¹HNMR (300 MHz, dimethylsulfoxide-d₆) δ 8.57 (bs, 1H), 8.48 (bs, 1H), 7.69(dd, 1H), 7.54 (d, 1H), 7.37 (d, 2H), 7.08 (d, 1H), 7.07 (d, 2H), 6.80(dd, 1H), 6.55 (bs, 1H), 6.23 (d, 2H), 6.03 (d, 1H), 5.59 (d, 1H), 3.86(dd, 2H), 3.24 (m, 8H), 2.81 (bs, 2H), 2.35-2.15 (m, 6H), 1.97 (bs, 2H),1.93 (m, 1H), 1.65 (d, 2H), 1.42 (t, 2H), 1.35-1.21 (m, 2H), 0.95 (s,6H).

EXAMPLE 3804-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(2,6-diaminopyridin-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 373E for EXAMPLE372F in EXAMPLE 379. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.36 (d,1H), 8.34 (t, 1H), 7.70 (dd, 1H), 7.62 (d, 1H), 7.37 (d, 2H), 7.36 (t,1H), 7.09 (d, 1H), 7.08 (d, 2H), 6.97 (d, 1H), 6.64 (dd, 1H), 6.28 (d,1H), 5.21 (bs, 4H), 3.84 (dd, 2H), 3.25 (m, 2H), 3.06 (m, 4H), 2.76 (m,2H), 2.29-2.15 (m, 8H), 1.98 (bs, 2H), 1.91 (m, 1H), 1.63 (d, 2H), 1.41(t, 2H), 1.34-1.17 (m, 2H), 0.95 (s, 6H).

EXAMPLE 3812-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 264A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,diraeihylsulfoxide-d₆)δ 11.78-11.08 (m, 1H), 8.35 (s, 1H), 8.07 (s, 1H),7.73 (d, 1H), 7.54-7.43 (m, 2H), 7.36 (d, 3H), 7.07 (d, 2H), 6.65 (d,1H), 6.18 (d, 3H), 4.13 (d, 2H), 3.88 (d, 2H), 3.35 (d, 2H), 3.14 (s,4H), 2.99-2.78 (m, 2H), 2.08 (t, 9H), 1.66 (d, 2H), 1.45-1.22 (m, 4H),0.94 (s, 6H).

EXAMPLE 3822-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-3yl}amino)-3-nitrophenyl]sulfonyl}benzamideEXAMPLE 382A (R)-1-(1,3-difluoropropan-2-yl)piperidin-3-amine hydrogenchloride

A solution of (R)-tert-butylpiperidin-3-ylcarbamate (0.500 g),1,3-difluoropropan-2-one (0.258 g) and sodium triacetoxyhydroborate(0.794 g) were stirred together in dichloromethane (5 mL) overnight. Thereaction was quenched with saturated aqueous NaHCO₃ (10 mL) andextracted with dichloromethane (30 mL). The organic layer was washedwith brine (20 mL), dried over magnesium sulfate, filtered, andconcentrated. The crude material was treated with HCl (4.0 M dioxane, 2mL) in methanol (2 mL). After stirring for 2 hours, the reaction wasconcentrated to provide the title compound.

EXAMPLE 382B(R)-4-(1-(1,3-difluoropropan-2-yl)piperidin-3-ylamino)-3-nitrobenzenesulfonamide

To EXAMPLE 382A (0.590 g) and 4-chloro-3-nitrobenzenesulfonamide (0.611g) in dioxane (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.641mL) and the reaction heated to 90° C. The reaction was concentrated,loaded onto silica gel (Reveleris 80 g) and eluted using a gradient of35% to 100% ethyl acetate/hexanes over 30 minutes to give the titlecompound.

EXAMPLE 382C2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-3yl}amino)-3-nitrophenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 382B for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsuifoxide-d₆) δ 11.62-11.06 (m, 1H), 8.91 (d, 1H), 8.60 (d, 1H),7.87 (d, 1H), 7.75 (d, 1H), 7.47-7.32 (m, 4H), 7.19 (d, 1H), 7.06 (d,2H), 6.65 (d, 1H), 6.18 (s, 3H), 4.64 (dt, 4H), 4.00 (s, 1H), 3.27-3.08(m, 5H), 2.90-2.58 (m, 6H), 2.20 (d, 6H), 1.97 (s, 2H), 1.60 (s, 4H),1.40 (s, 2H), 0.94 (s, 6H).

EXAMPLE 383 tert-butyl5-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamateEXAMPLE 383A 2-(2-Amino-5-bromo-pyridin-4-yloxy)-4-fluoro-benzoic acidmethyl ester

EXAMPLE 271A (600 mg), potassium bromide (300 mg), and ammoniummolybdate (85 mg) were added to acetic acid (6 mL). Sodium perboratetetrahydrate (387 mg) was added. The mixture stirred at room temperaturefor 16 hours and added to water. The pH was adjusted to 12 using 1 Maqueous sodium hydroxide, and the solution was extracted with ethylacetate. The extract was washed with brine, dried over anhydrous sodiumsulfate, filtered, concentrated and purified by flash columnchromatography on silica gel using 30-70% ethyl acetate in hexanes.

EXAMPLE 383B2-(5-Bromo-2-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-fluoro-benzoicacid methyl ester

EXAMPLE 383A (726 mg), di-tert-butyldicarbonate (557 mg), and4-(dimethylamino)pyridine (26 mg) were added to acetonitrile (15 mL) andstirred at room temperature for 16 hours. The solution was concentratedand purified by flash column chromatography on silica gel using 20%ethyl acetate in hexanes to proivde the title compound.

EXAMPLE 383C2-(5-Bromo-2-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-piperazin-1-yl-benzoicacid methylester

The title compound was prepared by substituting EXAMPLE 383B for EXAMPLE342D in EXAMPLE 342E.

EXAMPLE 383D2-(5-Bromo-2-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoicacid methyl ester

The title compound was prepared by substituting EXAMPLE 60D for4-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 383C fortert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 383E2-(5-Bromo-2-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoicacid

The title compound was prepared by substituting EXAMPLE 383D for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 383F tert-butyl5-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate

The title compound was prepared by substituting EXAMPLE 383E for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 9.62 (bs,1H), 8.58 (bs, 1H), 8.48 (bs, 1H), 8.18 (s, 1H), 7.72 (m, 1H), 7.59 (m,1H), 7.36 (d, 2H), 7.15-6.98 (m, 4H), 6.82 (d, 1H), 6.62 (bs, 1H), 3.87(d, 2H), 3.35-3.20 (m, 8H), 2.79 (m, 2H), 2.30-2.16 (m, 6H), 1.97 (bs,2H), 1.92 (m, 1H), 1.64 (d, 2H), 1.41 (t, 2H), 1.32 (s, 9H), 1.30 (m,2H), 0.95 (s, 6H).

EXAMPLE 3844-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 384A2-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluoro-benzoic acidmethyl ester

The title compound was prepared by substituting4-chloro-1H-pyrrolo[2,3-B]pyridin-5-ol for EXAMPLE 342C in EXAMPLE 342D.

EXAMPLE 384B2-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-piperazin-1-yl-benzoicacid methyl ester

The title compound was prepared by substituting EXAMPLE 384A for EXAMPLE342D in EXAMPLE 342E.

EXAMPLE 384C4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-benzoicacid methyl ester

The title compound was prepared by substituting EXAMPLE 60D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 384B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

EXAMPLE 384D4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-benzoicacid

The title compound was prepared by substituting EXAMPLE 384C for EXAMPLE1E in EXAMPLE 1F.

EXAMPLE 384E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 384D for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.07 (s,1H), 8.60 (t, 1H), 8.58 (d, 1H), 8.07 (s, 1H), 7.88 (dd, 1H), 7.65 (t,1H), 7.51 (d, 1H), 7.34 (d, 2H), 7.18 (d, 1H), 7.04 (d, 2H), 6.66 (dd,1H), 6.50 (dd, 1H), 6.03 (d, 1H), 3.84 (dd, 2H), 3.26 (m, 4H), 3.13-2.96(m, 4H), 2.73 (m, 2H), 2.16 (m, 6H), 1.95 (bs, 2H), 1,91 (m, 1H), 1.61(d, 2H), 1.38 (t, 2H), 1.36-1.21 (m, 2H), 0.92 (s, 6H).

EXAMPLE 3854-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-({6-[(2,2,2-trifluoro)amino]pyridin-3-yl}oxy)benzamideEXAMPLE 385A methyl2-(6-(tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino)pyridin-3-yloxy)-4-fluorobenzoate

The title compound was prepared by substituting1,1,1-trifluoro-2-iodoethane for methyliodide in EXAMPLE 377C

EXAMPLE 385B methyl2-(6-(tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino)pyridin-3-yloxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 385A for EXAMPLE377E in EXAMPLE 377F.

EXAMPLE 385C methyl2-(6-(tert-butoxycarbonyl(2,2,2-trifluoroethyL)amino)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 385B fortert-butyl piperazine-1-carboxylate and EXAMPLE 60D for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

EXAMPLE 385D2-(6-tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 385C for EXAMPLE38G in EXAMPLE 38H.

EXAMPLE 385E tert-butyl5-(5-(4-((2-(4-chlorophenyl-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyranyl)methylamino)phenylsulfonylcarbamoyl)-phenoxy)pyridin-2-yl(2,2,2-trifluoroethyl)carbamate

The title compound was prepared by substituting EXAMPLE 385D for EXAMPLE110E in EXAMPLE 110F.

EXAMPLE 385F4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-({6-[(2,2,2-trifluoro)amino]pyridin-3-yl}oxy)benzamide

EXAMPLE 385E (20 mg) was dissolved in anhydrous dichloromethane andtrifluoroacetic acid (0.1 mL) was added. The reaction mixture wasstirred at room temperature for 1.5 hours. The solvent was removed undervacuum. The residue was dissolved in ethyl acetate, washed with NaHCO₃aqeuous solution and brine, dried over an hydrous sodium sulfate,filtered, and concentrated to provide the title compound. ¹H NMR (400MHz, dimethylsulfoxide-d₆) δ 8.56 (m, 2H), 7.86 (dd, 1H), 7.79 (d, 1H),7.69 (m, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.21 (m, 2H), 7.08 (m, 3H),6.63 (m, 2H), 6.13 (d, 1H), 4.13 (m, 2H), 3.85 (dd, 2H), 3.27 (m, 4H),3.06 (s, 4H), 2.74 (s, 2H), 2.18 (m, 6H), 1.97 (m, 3H), 1.61 (m, 2H),1.40 (t, 2H), 1.27 (m, 2H), 0.94 (s, 6H).

EXAMPLE 3862-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 386A trans-4-(aminomethyl)cyclohexanol

Tert-butyl trans-(4-hydroxycyclohexl)methylcarbamate (1 g) indichloromethane (10 ml) was treated with trifluoroacetic acid (10 ml) at0° C. for two hours. The reaction mixture was concentrated and theresidue was dried under vacuum to provide the title compound.

EXAMPLE 386B4-(trans-(4-hydroxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 386A for1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.

EXAMPLE 386C2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((4-hydroxycyclohexyl)methylamino)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 110F byreplacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 318E and EXAMPLE386B. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 8.61 (t, 1H), 8.58 (d,1H), 7.86 (dd, 1H), 7.75 (d, 1H), 7.44 (d, 1H), 7.40 (d, 1H), 7.36 (d,2H), 7.18 (d, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.18 (s, 3H), 4.52 (d,1H), 3.24-3.30 (m, 4H), 3.12 (s, 4H), 2.79 (s, 2H), 2.25 (s, 4H), 2.17(s, 2H), 1.97 (s, 2H), 1.79-1.89 (m, 2H), 1.75 (d, 2H), 1.50-1.64 (m,1H), 1.40 (t, 2H), 0.97-1.17 (m, 4H), 0.94 (s, 6H).

EXAMPLE 3872-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 387A methyl2-(6-amino-5-chloropyridin-3-yloxy)-4-(piperazin-1-yl)benozate

A solution of EXAMPLE 318C (8.90 g) and piperazine (10.34 g) indimethylsulfoxide (100 mL) was heated to 85° C. After stirring for 3hours, the reaction mixture was cooled, diluted with ethyl acetate (400mL), washed with water (2×250 mL) and brine (250 mL), dried overmagnesium sulfate, filtered, and concentrated to provide the titlecompound.

EXAMPLE 387B methyl2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydio-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate

To a solution of EXAMPLE 387A (0.344 g) and EXAMPLE 38E (0.238 g) indichloromethane (5 mL) was added sodium triacetoxyhydroborate (0.302 g)and the reaction stirred at room temperature overnight. The reaction wasquenched with saturated aqueous NaHCO₃ (10 mL) and extracted withdichloromethane (50 mL). The organic layers were combined, dried overmagnesium sulfate, filtered, and concentrated. Silica gel chromatography(Reveleris 40 g) eluting with a gradient of 10-75% ethyl acetate hexanesover 30 minutes (flow=40 ml/min) provided the title compound.

EXAMPLE 387C2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3yl)methyl)piperazin-1-yl)benzoicacid

To a solution of EXAMPLE 387B (0.300 g) in tetrahydrofuran (5 mL) andmethanol (1 mL) was added 1.0 M lithium hydroxide (1.506 mL) and thesuspension was heated to 55° C. After 3 hours, the reaction was cooled,diluted with dichloromethane (20 mL) and water (10 mL), and quenchedwith 1 N aqueous HCl (1.5 mL). The organic layer was separated and theaqueous layer was extracted with 20 ml of dichloromethane. The combinedorganic extracts were washed with brine(25 mL), dried over magnesiumsulfate, filtered, and concentrated to give the title compound.

EXAMPLE 387D2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 387B for EXAMPLE1F in EXAMPLE 1H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.40 (s,1H), 8.64 (t, 1H), 8.59 (d, 1H), 7.87 (dd, 1H), 7.75 (d, 1H), 7.47-7.35(m, 4H), 7.23 (d, 1H), 7.19-7.11 (m, 2H), 6.65 (dd, 1H), 6.18 (s, 3H),4.14 (s, 2H), 3.85 (dd, 2H), 3.44-3.21 (m, 4H), 3.11 (s, 4H), 2.87 (s,2H), 2.24 (s, 4H), 2.16 (s, 2H), 1.91 (s, 1H), 1.63 (d, 2H), 1.38-1.15(m, 8H).

EXAMPLE 388N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 277B for EXAMPLE1F and EXAMPLE 326A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.22 (s, 1H), 8.60 (d, 1H), 8.30 (d, 1H), 7.55(d, 1H), 7.38 (m, 4H), 7.29 (br d, 1H), 7.13 (d, 2H), 6.64 (d, 1H), 6.41(s, 1H), 6.09 (s, 1H), 4.53 (d, 2H), 4.10 (s, 2H), 3.78 (m, 2H), 3.60(m, 2H), 3.07 (v br s, 4H), 2.86 (br s, 2H), 2.25 (v br s, 4H), 2.15 (s,2H), 1.85 (m, 4H), 1.18 (s, 6H).

EXAMPLE 3892-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE1F and EXAMPLE 332A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.52-11.11 (m, 1H), 8.65 (s, 1H), 8.58 (d, 1H),7.87 (d, 1H), 7.74 (d, 1H), 7.47-7.32 (m, 4H), 7.22 (d, 1H), 7.06 (d,2H), 6.65 (d, 1H), 6.17 (s, 3H), 3.86-3.38 (m, 6H), 3.12 (s, 4H), 2.79(s, 2H), 2.61 (s, 1H), 2.21 (d, 6H), 1.97 (s, 3H), 1.65 (d, 1H), 1.40(s, 2H), 0.94 (s, 6H).

EXAMPLE 3902-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 387C for EXAMPLE1F and EXAMPLE 326A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.94-11.04 (m, 1H), 8.58 (d, 1H), 8.26 (d, 1H),7.75 (d, 1H), 7.48 (d, 1H), 7.40 (d, 3H), 7.16 (d, 2H), 6.66 (d, 1H),6.18 (d, 3H), 4.56 (d, 2H), 4.15 (s, 2H), 3.77 (dd, 2H), 3.67-3.51 (m,2H), 3.14 (s, 4H), 2.95 (s, 2H), 2.33 (s, 4H), 2.17 (s, 2H), 1.87 (td,4H), 1.20 (s, 6H).

EXAMPLE 3912-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({9-(4-chlorophenyl)-3-[2-fluoro-1-(fluoromethyl)ethyl]-3-azaspiro[5.5]undec-8-en-8-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 391A benzyl 4-(piperidin-1-ylmethylene)piperidine-1-carboxylate

To a solution of benzyl 4-formylpiperidine-1-carboxylate (22.35 g) intoluene (300 mL) was added piperidine (11.55 g). The mixture was stirredat reflux under a Dean-Stark trap overnight. The mixture was thenconcentrated under vacuum and the residue was used directly in the nextstep.

EXAMPLE 391B benzyl 9-oxa-3-azaspiro[5.5]undec-7-enc-3-carboxylate

To a solution of crude EXAMPLE 391A (35.5 g) in ethanol (300 mL) wasadded but-3-enone (8.71 g). The mixture was stirred at reflux overnight. Acetic acid (30 mL) was added to the mixture which was stirred atreflux again overnight. The mixture was then concentrated under vacuumand the residue was diluted with ethyl acetate (600 mL) and washed withwater, brine and dried over Na₂SO₄. After filtration and evaporation ofthe solvent, silica gel chromatography using 5-20% ethyl acetate inhexanes provided the title compound.

EXAMPLE 391C benzyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate

EXAMPLE 391B (21 g) and tetrahydrofuran (160 mL) were added to wet 5%Pt-C (3.15 g) in a 250 mL SS pressure bottle and the mixture was stirredfor 24 hours at 30 psi H₂. The mixture was filtered through a nylonmembrane and concentrated to afford the product.

EXAMPLE 391D benzyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of EXAMPLE 391C (23.66 g) in dichloromethane (350 mL) wasadded Dess-Martin Periodinane (33.1 g). The mixture was stirredovernight. The mixture was diluted with ethyl acetate (600 mL) andwashed with 2 N aqueous NaOH, water, and brine. After drying overNa₂SO₄, the mixture was filtered and concentrated to proivde the titlecompound.

EXAMPLE 391E benzyl9-chloro-8-formyl-3-azaspiro[5.5]undec-8-ene-3-carboxylate

Phosphorus oxychloride (5.68 mL) was added dropwise to a cooled (0° C.)solution of EXAMPLE 391D (18.37 g) in N,N-dimethylformaraide (20 mL) anddichloromethane (80 mL). The mixture was then stirred overnight beforeit was diluted with ethyl acetate (600 mL) and washed with aqueoussodium acetate, water (3×), and brine and dried over Na₂SO₄. Afterfiltration and concentration, the crude product was used directly in thenext reaction without further purification.

EXAMPLE 391F benzyl9-(4-chlorophenyl)-8-formyl-3-azaspiro[5.5]undec-8-ene-3-carboxylate

To a mixture of 4-chlorophenylboronic acid (11.34 g, 72.5 mmol), EXAMPLE391E (21.01 g), palladium(II) acetate(271 mg), K₂CO₃ (25.05 g) andtetrabutylammonium bromide (19.5 g) was added water (120 mL). Themixture was stirred at 50° C. overnight. The mixture was diluted withethyl acetate (400 mL) and washed with water (3×) and brine and driedover Na₂SO₄. After filtration and concentration, the residue was loadedon a column and eluted with 5-20% ethyl acetate in hexane to provide thetitle compound.

EXAMPLE 391G benzyl8-((4-(3-(6-amino-5-Chloropyridin-3-yloxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-9-(4-chlorophenyl-3-azaspiro[5.5]undec-8-ene-3-carboxylate

To a solution of EXAMPLE 387A (498 mg) in dichloromethane (10 mL) wasadded EXAMPLE 391F (582 mg) and sodium triacetoxyborohydride (436 mg).The mixture was stirred overnight. The reaction mixture was diluted withethyl acetate (300 mL) and washed with 2 N aqueous NaOH and brine, anddried over Na₂SO₄. Filtration, evaporation of the solvent, and flashchromatography (2% methanol in dichloromethane) provided the titlecompound.

EXAMPLE 391H methyl2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((9-(4-chlorophenyl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoate

To a solution of EXAMPLE 391G (1.02 g) in ethanol (20 mL) was added Pd/C(10% , 150 mg). The mixture was stirred for 5 hours. The mixture wasfiltered and the filtrate was concentrated to provide the titlecompound.

EXAMPLE 391I2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoicacid

To a solution of EXAMPLE 391H (318 mg) in dichloromethane (4 mL) wasadded 1,3-difluoropropan-2-one (282 mg) and sodium acetoxyborohydride(318 mg). The mixture was stirred overnight. The reaction mixture wasdiluted with ethyl acetate (300 mL) and washed with 2 N aqueous NaOH andbrine, and dried over Na₂SO₄. Filtration and concentration gave thecrude product which was dissolved in tetrahydrofuran (10 mL), methanol(5 mL) and water (5 mL). LiOH.H₂O (450 mg) was added and the mixture wasstirred overnight. The mixture was neutralized with 2N aqueous HCl andextracted with ethyl acetate (300 mL) and dichloromethane (300 mL)respectively. The organic extracts were combinedand dried over Na₂SO₄.Filtration and concentration provided the title compound.

EXAMPLE 391J2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({9-(4-chlorophenyl)-3-[2-fluoro-1-(fluoromethyl)ethyl]-3-azaspiro[5.5]undec-8-en-8-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1H, replacingEXAMPLE 1F with EXAMPLE 391I. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ8.62 (t, 1H), 8.57 (d, 1H), 7.86 (dd, 1H), 7.75 (d, 1H), 7.44 (d, 1H),7.36 (m, 4H), 7.21 (d, 1H), 7.08 (m, 3H), 6.65 (dd, 1H), 6.17 (m, 3H),4.69 (d, 2H), 4.53 (d, 2H), 3.85 (dd, 2H), 3.10 (m, 6H), 2.71 (m, 9H),2.25 (m, 8H), 2.06 (m, 2H), 1.91 (m, 1H), 1.62 (m, 2H), 1.48 (m, 4H),1.25 (m, 2H).

EXAMPLE 3922-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 392A2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as in EXAMPLE 391I by replacingdifluoropropan-2-one with acetone.

EXAMPLE 392B2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as in EXAMPLE 1H by replacing EXAMPLE 1Fwith EXAMPLE 392A. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.40 (m,2H), 7.71 (dd, 1H), 7.60 (d, 1H), 7.54 (d, 1H), 7.38 (d, 3H), 7.11 (d,4H), 7.00 (d, 1H), 6.62 (dd, 1H), 6.28 (d, 1H), 5.88 (s, 2H), 3.84 (dd,3H), 3.04 (m, 7H), 2.73 (m, 4H), 2.23 (m, 9H), 1.90 (m, 2H), 1.63 (m,10H), 1.27 (m, 6H)

EXAMPLE 3932-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamideEXAMPLE 393A tert-butyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate

1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.0 g) intetrahydrofuran (10 mL) at 0° C. was treated with a 1N solution ofLiAlH₄ (2.54 mL), stirred 2 hours at room temperature, treatedsequentially dropwise with water (0.2 mL) and a 2 N aqueous solution ofNaOH (0.6 mL) and stirred for 1 hour. The solid was removed byfiltration through a pad of diatomaceous earth, rinsing with ethylacetate. The filtrate was washed with water and brine, dried (MgSO₄),filtered and concentrated to proivde the title compound.

EXAMPLE 393B tert-butyl4-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)-4-fluoropiperidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 393A for(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 303A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 264A.

EXAMPLE 393C5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide,2-trifluoroacetic acid salt

The title compound was prepared by substituting EXAMPLE 393B for EXAMPLE1A in EXAMPLE 1B.

EXAMPLE 393D5-chloro-6-((1-(2-(dimethylamino)acetyl)-4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide

5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide,2-trifluoroacetic acid (0.131 g), 2-(dimethylamino)acetyl chloride,hydrochloric acid (0.139 g), and sodium carbonate (0.048 g) werecombined in a 5-mL vial with N,N-dimethylformamide (3 mL) and stirredovernight at room temperature. Additional sodium carbonate (0.048 g) wasadded followed by 2-(dimethylamino)acetyl chloride, hydrochloric acid(0.139 g) and stirring was continued over a second night. The reactionmixture was concentrated under high vacuum, slurried in CH₂CL₂,filtered, concentrated, chromatographed on amine functionalized silicagel with 0 to 4% methanol in CH₂CL₂ as the eluent and dried in a vacuumoven at 80° C.

EXAMPLE 393E2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 318E for EXAMPLE110E and EXAMPLE 393D for EXAMPLE 1G in EXAMPLE 110F. ¹H NMR (500 MHz,PYRIDINE-d₅) δ 9.14 (d, 1H), 8.75 (d, 1H), 8.08 (d, 1H), 8.02 (d, 1H),7.45 (m, 2H), 7.40 (d, 1H), 7.09 (m, 2H), 6.73 (dd, 1H), 6.53 (d, 1H),4.66 (d, 1H), 4.57 (d, 1H), 4.53 (d, 1H), 4.08 (d, 1H), 3.40 (m, 2H),3.27 (m, 1H), 3.11 (m, 5H), 2.80 (s, 2H), 2.33 (s, 6H), 2.29 (t, 2H),2.19 (m, 4H), 2.06 (m, 2H), 1.99 (s, 2H), 1.84 (m, 2H), 1.41 (t, 2H),0.95 (s, 6H).

EXAMPLE 3942-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 318E for EXAMPLE 1Eand EXAMPLE 357B for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.58 (d, 1H), 8.41 (d, 1H), 7.89 (d, 1H), 7.73(d, 1H), 7.44 (d, 1H), 7.37 (m, 3H), 7.19 (d, 1H), 7.06 (d, 2H), 6.65(dd, 1H), 6.18 (m, 3H), 4.67 (d, 2H), 4.58 (d, 2H), 4.30 (m, 1H), 3.11(m, 5H), 2.95 (m, 2H), 2.78 (m, 4H), 2.23 (m, 7H), 1.97 (m, 2H), 1.72(m, 1H), 1.40 (t, 2H), 0.94 (s, 6H).

EXAMPLE 3952-[(2-amino-5-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 383F for EXAMPLE 372Fin EXAMPLE 379. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.61 (t, 1H),8.49 (d, 1H), 7.81 (s, 1H), 7.74 (dd, 1H), 7.54 (d, 1H), 7.37 (d, 2H),7.12 (d, 1H), 7.08 (d, 2H), 6.82 (dd, 1H), 5.65 (bs, 1H), 5.93 (bs, 2H),5.49 (s, 1H), 3.87 (dd, 2H), 3.31-3.19 (m, 8H), 2.84 (m, 2H), 2.40-2.15(m, 6H), 1.99 (bs, 2H), 1.94 (m, 1H), 1.64 (d, 2H), 1.42 (t, 2H),1.35-1.21 (m, 2H), 0.95 (s, 6H).

EXAMPLE 3962-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 396A tert-butyl(4,4-difluorocyclohexyl)methylcarbamate

Tert-butyl (4-oxocyclohexyl)methylcarbamate (5 g) anddiethylaminosulphurtrifluoride (7.45 g) were stirred in dichloromethane(100 mL) for 24 hours. The mixture was quenched with pH 7 buffer (100mL), and poured into ether (400 mL). The resulting solution wasseparated, and the organic layer was washed twice with water and brine,and concentrated to give the crude product and fluoroolefin 3:2 ratio.The crude product was taken up in tetrahydrofuran (70 mL) and water (30mL), and N-methylmorpholine-N-oxide (1.75 g) and OsO₄ (2.5 wt % solutionin t-butanol) were added, and the mixture was stirred for 24 hours.Na₂S₂O₃ (10 g) was then added, and the mixture was stirred for 30minutes. The mixture was then diluted with ether (300 mL), and theresulting solution was separated, and rinsed twice with water and brine,and concentrated. The crude product was chromatographed on silica gelusing 5-10% ethyl acetate in hexanes to give the title compound.

EXAMPLE 396B (4,4-difluorocyclohexyl)methanamine

A solution of EXAMPLE 396A (3 g) in dichloromethane (35 mL),trifluoroacetic acid (15 mL), and triethylsilane (1 mL) was stirred for2 hours. The solution was concentrated, then condensed from toluene, andleft under high vacuum for 24 hours. The semi-solid was taken up inether/hexane and filtered to give the title compound as its TFA salt.

EXAMPLE 396C4-((4,4-difluorocyclohexyl)methylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 396B for1-isopropylpiperidin-4-amine in EXAMPLE 41A.

EXAMPLE 396D2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 318E for EXAMPLE 1Fand EXAMPLE 396C for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.67 (t, 1H), 8.58 (d, 1H), 7.86 (dd, 1H), 7.75(d, 1H), 7.45 (d, 1H), 7.40 (d, 1H), 7.35 (d, 2H), 7.22 (d, 1H), 7.06(d, 2H), 6.65 (dd, 1H), 6.17 (m, 3H), 3.35 (m, 2H), 3.12 (v br m, 4H),2.80 (br s, 2H), 2.25 (v br m, 4H), 2.17 (br t, 2H), 2.01 (br m, 2H),1.98 (s, 2H), 1,80 (br m, 5H), 1.40 (t, 2H), 1.28 (br m, 2H), 0.93 (s,6H).

EXAMPLE 397[3-chloro-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)-2-iminopyridin-1(2H)-yl]methyldihydrogen phosphate

A mixture of EXAMPLE 318F (93 mg), di-tert-butylchloromethylphosphate(82 mg) and N,N-diisopropylethylamine (0.12 mL) in 3 mL of acetonitrilewas heated at 90° C. in a Bitage microwave synthesizer 3 hours, cooledand concentrated. The residue was dissolved in dichloromethane (3 mL)and trifluoroacetic acid (2 mL) was added. The resulting solution wasstirred at room temperature and concentrated. The residue was dissolvedin a mixture of dimethylsulfoxide and methanol, purified by HPLC,eluting with 40-55% acetonitrile in 0.1% trifluoroacetic acid in waterover 40 minutes. The title compound was obtained as a TFA salt. ¹H NMR(500 MHz, dimethylsulfoxide-d₆) δ 8.67 (t, 1H), 8.59 (d, 1H), 8.21 (d,1H), 8.12 (d, 1H), 7.89 (dd, 1H), 7.50 (d, 1H), 7.41 (d, 2H), 7.28 (d,1H), 7.11 (d, 2H), 6.74 (dd, 1H), 6.39 (d, 1H), 5.77 (d, 2H), 3.86 (dd,4H), 3.32-3.42 (m, 4H), 3.27 (dd, 4H), 2.99 (s, 4H), 2.23 (s, 2H), 2.04(s, 2H), 1.91 (dd, 1H), 1.63 (d, 2H), 1.47 (t, 2H), 1.20-1.33 (m, 2H),0.96 (s, 6H).

EXAMPLE 3982-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideEXAMPLE 398A 4′-chloro-3-hydroxybiphenyl-2-carbaldehyde

2-Bromo-6-hydroxybenzaldehyde (2.0 g), 4-chlorophenylboronic acid (1.86g) and tetrakis(triphenylphosphine)palladium(0) (0.575 g) were suspendedin a mixed solvent of dimethoxyethane (7 mL), ethanol (2 mL) and 2 NNa₂CO₃ aqueous soltuion (5 mL). The reaction mixture was heated at 90°C. for 2 hours. The reaction mixture was diluted with ethyl acetate andpoured into water. The organic layer was washed with water and withbrine, dried over anhydrous sodium sulfate, filtered, and concentrated.The resulting solid was triturated with methanol anjd filtered to affordthe title compound.

EXAMPLE 398D4′-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-carbaldehyde

EXAMPLE 398A (250 mg) and 2-chloro-N,N-dimethylethanamine hydrochloridesalt (310 mg) was dissolved in mixed solvent of dichloromethane (5 mL)and 50% sodium hydroxide aqueous soltuion (0.5 mL), followed by additionof tetrabutylammonium iodide (79 mg). The reaction mixture was stirredat room temperature overnight. The reaction mixture was diluted withethyl acetate and washed with water and brine. The organic phase wasdried over anhydrous sodium sulfate, filtered, and concentrated. Flashcolumn purification was performed 0-5% methanol/dichloromethane toafford the title compound.

EXAMPLE 398C2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 398B for EXAMPLE 1F inEXAMPLE 1H. ¹H NMR (300 MHz, DMSO) δ 11.67-11.61 (m, 1H), 9.91-9.71 (m,1H), 9.13-8.93 (m, 1H), 8.68-8.65 (m, 1H), 8.59 (d, 1H), 7.85 (s, 1H),7.75 (d, 1H), 7.54 (d, 3H), 7.47 (d, 1H), 7.41 (d, 1H), 7.38 (s, 2H),7.24 (d, 2H), 6.98 (s, 1H), 6.71-6.64 (m, 1H), 6.21 (s, 2H), 4.45 (s,8H), 3.83 (s, 3H), 3.60 (s, 3H), 3.31 (d, 6H), 2.92 (s, 4H), 1,99-1.82(m, 1H), 1.60 (s, 2H), 1.36-1.18 (m, 2H).

EXAMPLE 3992-[(6-amino-5-chloropyridin-3-yl)oxy]-N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamideEXAMPLE 399A(R)-5-chloro-6-((1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 400B (278 mg) and 1,3-difluoropropan-2-one (94 mg) weresuspended in 1,2-dichloroethane (10 mL). N,N-Dimethylformamide (1.5 mL)was added drop wise until a milky suspension formed. The reactionmixture was stirred at room temperature for 15 minutes followed by theaddition of sodium triacetoxyborohydride (424 mg). The reaction mixturewas stirred at room temperature overnight. The solvent was removed undervacuum. Flash column purificationwith 2.5-5% methanol/dichloromethaneprovided the title compound.

EXAMPLE 399B2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

This example was prepared by substituting EXAMPLE 318E for EXAMPLE 110Eand EXAMPLE 399A for EXAMPLE 1G in EXAMPLE 110F. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.37 (d, 1H), 8.06 (d, 1H), 7.62 (d, 1H), 7.54(d, 1H), 7.36 (m, 2H), 7.17 (d, 1H), 7.07 (m, 2H), 6.63 (dd, 1H), 6.27(d, 1H), 5.92 (bs, 2H), 4.65 (m, 2H), 4.53 (m, 2H), 4.28 (m, 2H), 3.07(s, 4H), 2.90 (m, 2H), 2.76 (m, 4H), 2.58 (m, 2H), 2.20 (m, 6H), 1.99(m, 3H), 1.54 (m, 1H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 4002-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamideEXAMPLE 400A (R)-tert-butyl3-((3-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)pyrrolidine-1-carboxylate

This example was prepared by substituting (R)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 303B.

EXAMPLE 400B(R)-5-chloro-6-(pyrrolidin-3-ylmethoxy)pyridine-3-sulfonamide

EXAMPLE 400A (480 mg) was dissolved in anhydrous tetrahydrofuran (10 mL)followed by addition of hydrogen chloride in dioxane solution (4 M, 2.5mL). The reaction mixture was stirred at room temperature overnight. Thesolvent was removed under vacuum to provide the title compound.

EXAMPLE 400C(R)-5-chloro-6-((1-(2,2-difluoroethyl)pyrrolidin-3-yl)methoxy)pyridine-3-sulfonamide

A reaction mixture of EXAMPLE 400B (353 mg), 1,1-difluoro-2-iodoethane(268 mg) and Na₂CO₃ (283 mg) in N,N-dimethylformamide (10 mL) was heatedat 80° C. overnight. The reaction mixture was cooled to room temperatureand diluted with ethyl acetate. The organic phase was washed with waterand brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. Flash column purification with 2.5-3%methanol/dichloromethane provided the title compound.

EXAMPLE 400D2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

This example was prepared by substituting EXAMPLE 318E for EXAMPLE 110Eand EXAMPLE 400C for EXAMPLE 1G in EXAMPLE 110F. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.37 (d, 1H), 8.05 (d, 1H), 7.62 (d, 1H), 7.54(d, 1H), 7.36 (m, 2H), 7.17 (d, 1H), 7.07 (d, 2H), 6.62 (dd, 1H), 6.27(d, 1H), 6.07 (m, 3H), 4.27 (m, 2H), 3.07 (s, 4H), 2.83 (m, 5H), 2.64(m, 3H), 2.20 (m, 6H), 1.99 (m, 4H), 1.54 (m, 1H), 1.41 (t, 2H), 0.94(s, 6H).

EXAMPLE 401Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamideEXAMPLE 401A 2-(trans-4-(aminomethyl)cyclohexyl)acetonitrile

To a solution oftert-butyl(trans-4-(cyanomethyl)cyclohexyl)methylcarbamate (500 mg) indichloromethane (5 mL) was slowly added trifluoroacetic acid (3 mL) at0° C. The mixture was warmed to room temperature, stirred for 1 hour andconcentrated. The residue was dried under vacuum to provide the titlecompound.

EXAMPLE 401B4-((trans-4-cyanocyclohexyl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 401A for1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.

EXAMPLE 401CTrans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared as described in EXAMPLE 110F byreplacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 318E and EXAMPLE401B. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 8.63 (t, 1H), 8.58 (d,1H), 7.85 (dd, 1H), 7.75 (d, 1H), 7.44 (d, 1H), 7.40 (d, 1H), 7.36 (d,2H), 7.19 (d, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.19 (s, 3H), 3.24-3.31(m, 4H), 3.12 (s, 4H), 2.79 (s, 2H), 2.58-2.69 (m, 1H), 2.25 (s, 4H),2.17 (s, 2H), 1.92-2.07 (m, 4H), 1.79 (d, 2H), 1.60-1.73 (m, 1H),1.34-1.55 (m, 4H), 0.97-1.12 (m, 2H), 0.94 (s, 6H).

EXAMPLE 4022-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamideEXAMPLE 402A5-bromo-3-fluoro-2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine

This example was prepared by substituting EXAMPLE 296C for(tetrahydro-2H-pyran-4-yl)methanol and 5-bromo-2,3-difluoropyridine for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 264A.

EXAMPLE 402B tert-butyl5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-ylcarbamate

EXAMPLE 402A (0.658 g), tert-butylcarbamate (0.300 g), palladium(II)acetate (0.024 g), 4.5-bis(diphenylphosphino)-9,9-dimethylxanthene(0.093 g) and cesium carbonate (1.044 g) were combined in a 20 mL vialwith dioxane (10.7 ml). The vial was flushed with nitrogen, capped andstirred at 100° C. overnight. The reaction mixture was diluted withethyl acetate, washed with water and brine, dried (MgSO₄), filtered,concentrated and chromatographed on silica gel with 20% ethyl acetate inhexanes as eluent.

EXAMPLE 402C5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonylchloride

Under ice-cooling, thionyl chloride (1.563 mL) was added dropwise over20 minutes to water (9 mL). The mixture was stirred for 12 hours to givea SO₂-containing solution. Separately, EXAMPLE 402B (0.295 g) was addedto a mixture of dixane (3.2 mL) and concentrated HCl (8 ml) at 0° C. Thesolution was stirred for 15 minutes, treated with a solution of sodiumnitrite (0.065 g) in water (2 mL) dropwise at 0° C. and stirred at 0° C.for 3 hours. The SO₂-containing solution was cooled to 0° C., treatedsequentially with copper(I) chloride (0.042 g) and the diazotizedmixture, and stirred for 30 minutes. The reaction mixture was thenextracted with ethyl acetate and the orgnaic layer was dried (MgSO₄),filtered and concentrated. The residue was chromatographed on silica gelwith 5-10% ethyl acetate in hexanes as the eluent.

EXAMPLE 402D5fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 402C (0.08 g, ) in isopropanol (2 mL) at 0° C. was treated withammonium hydroxide (1.70 mL) and stirred overnight. The reaciton mixturewas concentrated, slurried in water, filtered, rinsed with water anddried under vacuum.

EXAMPLE 402E2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 402D for EXAMPLE 1Gand EXAMPLE 318E for EXAMPLE 110E in EXAMPLE 110F. ¹H NMR (400 MHz,pyridine-d₅) δ 9.05 (d, 1H), 8.49 (dd, 1H), 8.03 (d, 1H), 8.00 (d, 1H),7.45 (m, 2H), 7.39 (d, 1H), 7.09 (m, 2H), 6.73 (dd, 1H), 6.52 (d, 1H),4.59 (d, 2H), 3.81 (m, 4H), 3.12 (m, 4H), 2.80 (s, 2H), 2.29 (t, 2H),2.18 (m, 4H), 1.99 (s, 2H), 1.88 (m, 4H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 4032-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamideEXAMPLE 403A

EXAMPLE 393C (0.263 g), 1,1-difluoro-2-iodoethane (0.23 g), and sodiumcarbonate (0.254 g) were combined in a 20 mL vial withN,N-dimethylformamide (6 mL) and the mixture stirred at 70° C.overnight. The reaction mixture was concentrated under high vacuum,chromatographed on silica gel with 0-5% methanol in dichloromethane asthe eluent, and dried overnight in a vacuum oven 80° C.

EXAMPLE 403B2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

This example was prepared by substituting EXAMPLE 403A for EXAMPLE 1Gand EXAMPLE 318E for EXAMPLE 110E in EXAMPLE 110F. ¹H NMR (400 MHz,pyridine-d₅) δ 9.15 (d, 1H), 8.75 (d, 1H), 8.02 (d, 1H), 8.00 (d, 1H),7.45 (m, 2H), 7.38 (d, 1H), 7.09 (m, 2H), 6.72 (dd, 1H), 6.50 (d, 1H),6.18 (tt, 1H), 4.55 (d, 2H), 3.12 (m, 4H), 2.80 (m, 6H), 2.60 (td, 2H),2.28 (t, 2H), 2.17 (m, 4H), 1.93 (m, 6H), 1.41 (t, 2H), 0.95 (s, 6H).

EXAMPLE 4042-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamideEXAMPLE 404A3-chloro-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

To a solution of EXAMPLE 296C (0.175 g) in tetrahydrofuran (5 ml) wasadded sodium hydride (0.209 g) and the reaction stirred at roomtemperature for 15 minutes, 3-Chloro-4-fluorobenzenesulfonamide(0.273 g)was added and the reaction stirred for 3 hours. to the thick suspensionwas added tetrahydrofuran (2 ml) and N,N-dimethylformamide (3 ml). Thereaction was stirred for 3 hours at 60° C. then poured intodichloromethane (50 ml) and 1N aqueous HCl (50 ml). The organic layerwas washed with brine (35 ml) dried over magnesium sulfate, filtered,and concentrated. Silica gel chromatography (Reveleris 40 g) elutingwith a gradient of 10-100% ethyl acetate/hexanes over 30 minutes(flow=40 ml/minute) gave the title compound.

EXAMPLE 404B2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

This example was prepared by substituting EXAMPLE 318E for EXAMPLE 1Fand EXAMPLE 404A for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (300 MHz, DMSO) δ11.44-11.17 (m, 1H), 7.91 (d, 1H), 7.83 (dd, 1H), 7.77 (d, 1H), 7.44 (d,2H), 7.35 (dd, 3H), 7.06 (d, 2H), 6.66 (d, 1H), 6.19 (d, 3H), 4.31 (d,2H), 3.84-3.73 (m, 2H), 3.66-3.55 (m, 2H), 3.13 (s, 4H), 2.81 (s, 2H),2.26 (s, 4H), 2.17 (s, 2H), 2.02-1.74 (m, 6H), 1,41 (s, 2H), 0.94 (s,6H).

EXAMPLE 4052-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamideEXAMPLE 405A 5-nitro-3-(trifluoromethyl)pyridin-2-ol

3-(Trifluoromethyl)pyridin-2-ol (2.3 g) was added to concentratedsulfuric acid (15 mL) at 0° C. The mixture was stirred at 0° C. for 5minutes. To this solution was added nitric acid (fuming, 6 mL) dropwiseover 5 minutes. The reaction mixture was stirred at room temperature for2 hours, and then heated at 50° C. for 3 hours. After cooling, thereaction mixture was poured into ice (200 g), and the mixture wasextracted with ethyl acetate three times. The combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentratedunder reduced pressure to give the title compound.

EXAMPLE 405B 2-chloro-5-nitro-3-(trifluoromethyl)pyridine

A mixture of EXAMPLE 405A (1.69 g), phosphorus pentachloride (2.03 g),and phosphoryl trichloride (0.97 mL) was heated at 90° C. for 3 hours.After cooling, the reaction mixture was poured into ice, and extractedwith ethyl acetate three times. The extract was washed with brine, driedover MgSQ₄, filtered, and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica geleluting with 1:9 ethyl acetate\hexanes to give the title compound.

EXAMPLE 405C

A mixture of iron (1.5 g) and ammonium chloride (2.38 g) in water (40mL) was stirred at room temperature for 5 minutes. To this suspensionwas added EXAMPLE 405B in methanol (40 mL). The reaction mixture wasstirred at room temperature for 1 hour. More iron (1.8 g) was added tothe reaction mixture, and it was stirred for another 3 hours. The solidfrom the reaction mixture was filtered off, and the filtrate waspartitioned between water and ethyl acetate. The combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel eluting with 1:4 ethyl acetate\hexanes togive the title compound.

EXAMPLE 405D 6-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride

Under ice-cooling, thionyl chloride (4 mL) was added dropwise over 20minutes to water (27 mL). The mixture was stirred overnight for 12 hoursto give a SO₂ containing solution. Separately, EXAMPLE 405C (1.14 g) indioxane (5 mL) was added to concentrated HCl (20 mL) at 0° C. Thesolution was stirred for 5 minutes. To this suspension/solution wasadded sodium nitrite (0.44 g) in water (6 mL) dropwise at 0° C. Thesolution stirred at 0° C. for 3 hours. to the SO₂ containing solutionwas added copper(I) chloride (0.115 g). Then, to this solution was addedthe diazotized EXAMPLE 405C at 0° C. The solution was stirred for 30minutes. The reaction mixture was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel eluting with 1:20ethyl acetate hexanes to give the title compound.

EXAMPLE 405E 6-chloro-5-(trifluoromethyl)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 405D for5-bromo-6-chloropyridine-3-sulfonyl chloride in EXAMPLE 305A.

EXAMPLE 403F tert-butyl4-fluoro-4-((5-sulfamoyl-3-(trifluoromethyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate

This example was prepared by substituting EXAMPLE 405E for EXAMPLE 305Aand EXAMPLE 341A for (1,4-dioxan-2-yl)methanol in EXAMPLE 305B.

EXAMPLE 405G6-((4-fluoropiperidin-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 405F for EXAMPLE 400Ain EXAMPLE 400B.

EXAMPLE 405H6-((1-(1,3-difluoropropan-2-yl)-4-fluooropiperidin-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 405G for EXAMPLE 400Bin EXAMPLE 399A.

EXAMPLE 405I2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 318E for EXAMPLE 110Eand EXAMPLE 405 H for EXAMPLE 1G in EXAMPLE 110F. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.62 (d, 1H), 8.29 (d, 1H), 7.57 (m, 2H), 7.36(d, 2H), 7.09 (m, 3H), 6.62 (dd, 1H), 6.29 (d, 1H), 5.86 (bs, 2H), 4.67(d, 2H), 4.53 (m, 4H), 3.08 (m, 5H), 2.74 (m, 6H), 2.19(m, 6H), 1.89 (m,6H), 1.41 (t, 2H), 0.94 (s, 6H).

EXAMPLE 4064-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[2-(1H-pyrazol-4-yl)phenoxy]benzamideEXAMPLE 406A2-(2-bromophenoxy)-4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

The title compound was prepared as described is EXAMPLE 110F byreplacing EXAMPLE 110E with EXAMPLE 42C.

EXAMPLE 406B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[2-(1H-pyrazol-4-yl)phenoxy]benzamide

A mixture of EXAMPLE 406A (57 mg), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(27.7 mg), dichlorobis(triphenylphosphine)palladium(II) (6.61 mg), K₂CO₃(0.2 ml) in a dimethoxyethane/ethanol/water (7:2:3) was heated at 160°C. for 10 minutes in a Biotage microwave synthesizer and concentrated.The residue was dissolved in dimethylsulfoxide:methanol (1:1) andpurified by HPLC, eluting with 40-65% acetonitrile in 0.1% TFA waterover 40 minutes to provide the title compound as a TFAsalt. The TFA saltwas dissolved in dichloromethane and washed with saturated NaHCO₃aqueous solution. The organic layer was dried over Na₂SO₄, filtered, andconcentrated to proivde the title compound. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 12.87 (s, 1H), 11.55 (s, 1H), 8.58 (t, 1H), 8.47(d, 1H), 8.11 (s, 1H), 7.85 (s, 1H), 7.76 (dd, 1H), 7.59-7.67 (m, 1H),7.48 (d, 1H), 7.34 (d, 2H), 7.00-7.11 (m, 5H), 6.73 (dd, 1H), 6.67 (dd,1H), 6.08 (d, 1H), 3.85 (dd, 2H), 3.20-3.29 (m, 4H), 3.04 (s, 4H), 2.77(s, 2H), 2.17 (d, 6H), 1.96 (s, 2H), 1.80-1.92 (m, 1H), 1.55-1.70 (m,2H), 1.39 (t, 2H), 1.19-1.32 (m, 2H), 0.93 (s, 6H).

EXAMPLE 4072-[2-(2-aminopyridin-3-yl)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 406B byreplacing tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylatewith tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamate. ¹HNMR (400 MHz, dimethylsulfoxide-d₆) δ 8.57 (t, 1H), 8.41 (d, 1H), 7.92(dd, 1H), 7.74 (dd, 1H), 7.60 (d, 1H), 7.41 (d, 1H), 7.36 (d, 2H), 7.18(dd, 1H), 7.02-7.13 (m, 5H), 6.97 (t, 1H), 6.70 (dd, 1H), 6.61-6.67 (m,1H), 6.55 (d, 1H), 6.31 (d, 1H), 3.84 (dd, 2H), 3.21-3.30 (m, 4H), 3.15(s, 4H), 2.83 (s, 2H), 2.23-2.34 (m, 4H), 2.17 (s, 2H), 1.84-2.02 (m,3H), 1.63 (dd, 2H), 1.40 (t, 2H), 1.20-1.33 (m, 2H), 0.94 (s, 6H).

EXAMPLE 4084-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-[2-(1H-pyrazol-5-yl)phenoxy]benzamide

The title compound was prepared as described in EXAMPLE 406B byreplacing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate with1H-pyrazol-5-ylboronic acid. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ12.95 (s, 1H), 8.60 (s, 1H), 8.52 (s, 1H), 7.85 (s, 2H), 7.57-7.73 (m,1H), 7.48 (d, 1H), 7.22-7.37 (m, 4H), 7.00 -7.15 (m, 4H), 6.56-6.70 (m,2H), 5.96 (s, 2H), 3.85 (dd, 2H), 3.21-3.28 (m, 4H), 3.02 (s, 4H),2.70-2.85 (m, 2H), 2.10-2.30 (m, 5H), 1.83-1.99 (m, 3H), 1.62 (d, 2H),1.39 (t, 2H), 1.19-1.31 (m, 2H), 0.92 (s, 6H),

EXAMPLE 4092-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}suflonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamideEXAMPLE 409A (4,4-difluorocyclohexyl)methanol

Lithium aluminum hydride (0.24 g) was added to diethylether (15 mL), towhich was then added dropwise ethyl 4,4-difluorocyclohexanecarboxylate(1.0 g) in diethyl ether (2 mL), and the reaction was stirred at refluxunder nitrogen for 4 hours. The reaction was cooled to 0° C., followedby the careful addition of water (0.24 mL), 4N aqueous NaOH (0.24 mL),and additional water (0.72 mL). Then Na₂SO₄ (40 mL) were added and themixture was stirred for 30 minutes. After filtration throughdiatomaceous earth and concentration, the title compound was used in thenext step without further purification.

EXAMPLE 409B5-chloro-6-((4,4-difluorocyclohexyl)methoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 409A for(1,4-dioxan-2-yl)methanol and EXAMPLE 303A for EXAMPLE 305A in EXAMPLE305B.

EXAMPLE 409C2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

This example was prepared by substituting EXAMPLE 318E for EXAMPLE 122Cand EXAMPLE 409B for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.54 (s, 1H), 8.20 (2, 1H), 7.73 (d, 1H), 7.50(d, 1H), 7.37 (m, 3H), 7.07 (d, 2H), 6.66 (dd, 1H), 6.22 (s, 1H), 6.13(br s, 2H), 4.30 (d, 2H), 3.17 (v br m, 4H), 2.98 (v br s, 2H), 2.43 (vbr m, 4H), 2.18 (br t, 2H), 2.05 (br m, 3H), 1.98 (s, 2H), 1.8 (br m,4H), 1.43 (t, 2H), 1.35 (br m, 2H), 0.94 (s, 6H).

EXAMPLE 410N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

This example was prepared by substituting EXAMPLE 277B for EXAMPLE 122Cand EXAMPLE 409B for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.22 (s, 1H), 8.60 (d, 1H), 8.26 (d, 1H), 7.54(d, 1H), 7.38 (m, 4H), 7.29 (br d, 1H), 7.13 (d, 2H), 6.64 (d, 1H), 6.41(s, 1H), 6.09 (s, 1H), 4.30 (d, 2H), 4.10 (s, 2H), 3.05 (v br s, 4H),2.86 (v br s, 2H), 2.25 (v br s, 4H), 2.15 (s, 2H), 2.03 (br m, 2H),1.96 (br m, 1H), 1.85 (br m, 4H), 1.36 (m, 2H), 1.18 (s, 6H).

EXAMPLE 4114-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxyl]benzamide

This example was prepared by substituting EXAMPLE 154E for EXAMPLE 122Cand EXAMPLE 396C for EXAMPLE 11A in EXAMPLE 137. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.22 (s, 1H), 8.65 (t, 1H), 8.60 (d, 1H), 7.88(dd, 1H), 7.52 (d, 1H), 7.39 (dd, 1H), 7.35 (m, 4H), 7.18 (d, 1H), 7.03(d, 2H), 6.65 (dd, 1H), 6.21 (s, 1H), 6.08 (s, 1H), 3.04 (v br m, 4H),2.76 (br s, 2H), 2.20 (v br m, 4H), 2.13 (br t, 2H), 2.00 (br m, 3H),1.95 (s, 2H), 1.81 (br m, 6H), 1.39 (t, 2H), 1.24 (br m, 2H), 0.91 (s,6H).

1. A compound having Formula (I)

or a therapeutically acceptable salt, prodrug or salt of prodrugthereof, wherein A¹ is N or C(A²); A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹,C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹,NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂,NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹,SO₂N(R¹)₂,NHSO₂R¹,NR¹SO₂R¹,NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹,NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹,C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I,CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ orC(O)OR^(1A); B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹,OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹,NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)2, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); D¹ is H, R¹, OR¹, SR¹,S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹,C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹(O)R¹, NHC(O)NH₂,NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹,SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹,NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹,C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH3)R¹, F, Cl, Br, I,CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ orC(O)OR^(1A); E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹,OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹,NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹,NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂,N₃, OH, C(O)H,CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and Y¹ is H, CN,NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷, OR¹⁷,C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, SO₂R¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷,C(O)NH₂, C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷; or E¹ and Y¹,together with the atoms to which they are attached, are benzene,naphthylene, heteroarene cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; and A², B¹, and D¹ are independently selected H, R¹,OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHO(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)2, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F,Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(1A); or Y¹ and B¹, together with the atoms to whichthey are attached, are benzene, naphthylene, heteroarene cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; and A², D¹, and E¹are independently selected H, R¹, OR¹, SR¹, S(O)R¹, SO2R¹, C(O)R¹,C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹,NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂,NR¹C(O)NHR¹, NR¹(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO2R¹,NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH,C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR, C(NH)N(R¹)₂ NHSO₂NHR¹,NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂,N₃, OH, C(O)H,CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or A² and B¹,together with the atoms to which they are attached, are benzene,naphthylene, heteroarene cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; and D¹, E¹, and Y¹ are independently selected H, R¹,OR¹, SR¹, S(O)R¹, SO2R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHCC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F,Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(1A); or A² and D¹, together with the atoms to whichthey are attached, are benzene, naphthalene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; and B¹, E¹, and Y¹are independently selected H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹,C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹,NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂,NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹,NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH,C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹,NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂,N₃, OH, C(O)H,CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂or C(O)OR^(1A); R¹ is R², R³, R⁴or R⁵; R^(1A) is cycloalkyl, cycloalkenyl or cycloalkynyl; R² is phenyl,which is unfused or fused with benzene, heteroarene or R^(2A); R^(2A) iscycloalkane or heterocycloalkane; R³ is heteroaryl, which is unfused orfused with benzene, heteroarene or R^(3A); R^(3A) is cycloalkane orheterocycloalkane; R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(4A); R^(4A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵ is alkyl, alkenyl or alkynyl,each of which is unsubstituted or substituted with one or two or threeof independently selected R⁶, NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷,SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂,C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷,NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂,NHC(O)NHR⁷, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I; R⁶ is C₂-C₅-spiroalkyl, each of which isunsubstituted or substituted with OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl,Br, I, NH₂, NH(CH₃) or N(CH₃)₂; R^(6A) and R^(6B) are independentlyselected alkyl or, together with the N to which they are attached,R^(6C); R^(6C) is aziridin-l-yl, azetidin-l-yl, pyrrolidin-l-yl orpiperidin-l-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH; R⁷ is R⁸, R⁹, R¹⁰ or R¹¹; R⁸is phenyl, which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁹ is heteroaryl, which is unfused or fused withbenzene, heteroarene or R^(9A); R^(9A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹⁰ is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl each of which is unfused or fusedwith benzene, heteroarene or R^(10A); R^(10A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R¹¹ is alkyl,alkenyl or alkynyl, each of which is unsubstituted or substituted withone or two or three of independently selected R¹², OR¹², SR¹², S(O)R¹²,SO₂R¹², C(O)R¹², CO(O)R¹², OC(O)R¹², OC(O)OR¹², NH₂, NHR¹², N(R¹²)₂,NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹², NR¹²S(O)₂R¹², NHC(O)OR¹²,NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹², NHC(O)N(R¹²)₂, NR¹²C(O)NHR¹²,NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, C(O)NHOH, C(O)NHOR¹²,C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂, SO₂NHR¹², SO₂N(R¹²)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR¹², C(N)N(R¹²)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I; R¹² is R¹³, R¹⁴, R¹⁵ orR¹⁶; R¹³is phenyl, which is unfused or fused with benzene, heteroareneor R^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R¹⁴ is heteroaryl, which is unfused or fused withbenzene, heteroarene or R^(14A); R^(14A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹⁵ is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene, each of which is unfused orfused with benzene, heteroarene or R^(15A); R^(15A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁶ is alkyl,alkenyl or alkynyl; R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹; R¹⁸ is phenyl, which isunfused or fused with benzene, heteroarene or R^(18A); R^(18A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁹ isheteroaryl, which is unfused or fused with benzene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R²⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl each of which is unfused or fused with benzene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R²¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three of independently selected R²², OR²², SR²², S(O)R²², SO₂R²²,C(O)R²², CO(O)R²², OC(O)R²², OC(O)OR²², NH₂, NHR²², N(R²²)₂, NHC(O)R²²,NR²²C(O)R²², NHS(O)₂R²², NR²²S(O)₂R²², NHC(O)OR²², NR²²C(O)OR²²,NHC(O)NH₂, NHC(O)NHR²², NHC(O)N(R²²)₂, NR²²C(O)NHR²², NR²²C(O)N(R²²)₂,C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, C(O)NHOH, C(O)NHOR²², C(O)NHSO₂R²²,C(O)NR²²SO₂R²², SO₂NH₂, SO₂NHR²², SO₂N(R²²)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR²², C(N)N(R²²)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I; R²² is R²³, R²⁴ or R²⁵; R²³ is phenyl,which is unfused or fused with benzene, heteroarene or R^(23A); R^(23A)is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁴is heteroarene, which is unfused or fused with benzene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R²⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl each of which is unfused or fused with benzene,heteroarene or R^(25A); R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; Z¹ is R²⁶ or R²⁷; Z² is R²⁸, R²⁹or R³⁰; Z^(1A) and Z^(2A) are both absent or are taken together to formCH₂, CH₂CH₂ or Z^(12A); Z^(12A) is C₂-C₆-alkylene having one or two CH₂moieties replaced by NH, N(CH₃), S, S(O) or SO₂; L¹ is a R³⁷, OR³⁷,SR³⁷, S(O)R³⁷, SO₂R³⁷, C(O)R³⁷, CO(O)R³⁷, OC(O)R³⁷, OC(O)OR³⁷, NHR³⁷,C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO₂R³⁷, SO₂NH, SO₂NHR³⁷, C(N)NH,C(N)NHR³⁷; R²⁶ is phenylene, which is unfused or fused with benzene orheteroarene or R^(26A); R^(26A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R²⁷ is heteroarylene, which isunfused or fused with benzene or heteroarene or R^(27A); R^(27A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁸ isphenylene, which is unfused or fused with benzene, heteroarene orR^(28A); R^(28A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R²⁹ is heteroarylene, which is unfused or fused withbenzene or heteroarene or R^(29A); R^(29A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R³⁰ is cycloalkylene,cycloalkenylene, heterocycloalkylene or heterocycloalkenylene, each ofwhich is unfused or fused with benzene, heteroarene or R^(30A); R^(30A)is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R³⁷is a bond or R^(27A); R^(37A) is alkylene, alkenylene, or alkynylene,each of which is unsubstituted or substituted with one or two or threeindependently selected R^(37B), OR^(37B), SR^(37B), S(O)R^(37B),SO₂R^(37B), C(O)R^(37B), CO(O)R^(37B), OC(O)R^(37B), OC(O)OR^(37B), NH₂,NHR^(37B), N(R^(37B))₂, NHC(O)R^(37B), NR^(37B)C(O)R^(37B),NHS(O)₂R^(37B), NR^(37B)S(O)₂R^(37B), NHC(O)OR^(37B),NR^(37B)C(O)OR^(37B), NHC(O)NH₂, NHC(O)NHR^(37B), NHC(O)N(R^(37B))₂,NR^(37B)C(O)NHR^(37B), NR^(37B)C(O)N(R^(37B))₂, C(O)NH₂, C(O)NHR^(37B),C(O)N(R^(37B))₂, C(O)NHOH, C(O)NHOR^(37B), C(O)NHSO₂R^(37B),C(O)NR^(37B)SO₂R^(37B), SO₂NH₂, SO₂NHR^(37B), SO₂N(R^(37B))₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR^(37B), C(N)N(R^(37B))₂, CNOH, CNOCH₃,OH, (O),CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br and I substituents;R^(37B) is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; Z³ is R³⁸, R³⁹ orR⁴⁰; R³⁸ is phenyl, which is unfiised or fused with benzene, heteroareneor R^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R³⁹ is heteroaryl, which is unfused or fused withbenzene, heteroarene or R^(39A); R^(39A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴⁰ is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, each of which is unfused orfused with benzene, heteroarene or R^(40A); R^(40A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; wherein themoieties represented by ²⁶ and R²⁷ are substituted (i.e., if Z^(1A) andZ^(2A) are absent) or further substituted (i.e., if Z^(1A) and Z^(2A)are present) with one or two or three or four of independently selectedR⁴¹, OR⁴¹, SR⁴¹, S(O)R⁴¹, SO₂R⁴¹, C(O)R⁴¹, CO(O)R⁴¹, OC(O)R⁴¹,OC(O)OR⁴¹, NH₂, NHR⁴¹, N(R⁴¹)₂, NHC(O)R⁴¹, NR⁴¹C(O)R⁴¹, NHS(O)₂R⁴¹,NR⁴¹S(O)₂R⁴¹, NHC(O)OR⁴¹, NR⁴¹C(O)OR⁴¹, NHC(O)NH₂, NHC(O)NHR⁴¹,NHC(O)N(R⁴¹)₂, NR⁴¹C(O)NHR⁴¹, NR⁴¹C(O)N(R⁴¹)₂, C(O)NH₂, C(O)NHR⁴¹,C(O)N(R⁴¹)₂, C(O)NHOH, C(O)NHOR⁴¹, C(O)NHSO₂R⁴¹, C(O)NR⁴¹SO₂R⁴¹, SO₂NH₂,SO₂NHR⁴¹, SO₂N(R⁴¹)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁴¹, C(N)N(R⁴¹)₂,CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl,Br or I; R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵; R⁴² is phenyl, which is unfused orfused with benzene, heteroarene or R^(42A); R^(42A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁴³ is heteroaryl,which is unfused or fused with benzene, heteroarene or R^(43A); R^(43A)is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁴is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(44A);R^(44A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴⁵ is alkyl, alkenyl or alkynyl, each of which isunsubstitutcd or substituted with one or two or three of independentlyselected R⁴⁶, OR⁴⁶, SR⁴⁶, S(O)R⁴⁶, SO₂R⁴⁶, C(O)R⁴⁶, CO(O)R⁴⁶, OC(O)R⁴⁶,OC(O)OR⁴⁶, NH₂, NHR⁴⁶, N(R⁴⁶)₂, NHC(O)R⁴⁶, NR⁴⁶C(O)R⁴⁶, NHS(O)₂R⁴⁶,NR⁴⁶S(O)₂R⁴⁶, NHC(O)OR⁴⁶, NR⁴⁶C(O)OR⁴⁶, NHC(O)NH₂, NHC(O)NHR⁴⁶,NHC(O)N(R⁴⁶)₂, NR⁴⁶C(O)NHR⁴⁶, NR⁴⁶C(O)N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶,C(O)N(R⁴⁶)₂, C(O)NHOH, C(O)NHOR⁴⁶, C(O)NHSO₂R⁴⁶, C(O)NR⁴⁶SO₂R⁴⁶, SO₂NH₂,SO₂NHR⁴⁶, SO₂N(R⁴⁶)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR4 ⁴⁶, C(N)N(R⁴⁶)₂2, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F,Cl, Br or I; R⁴⁶ is alkyl, alkenyl, alkynyl, R⁴⁷, R⁴⁸ or R⁴⁹; R⁴⁷ isphenyl, which is unfased or fused with benzene, heteroarene or R^(47A);R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴⁸ is heteroaryl, which is unfused or fused withbenzene, heteroarene or R^(48A); R^(48A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴⁹ is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, each of which is unfused orfused with benzene, heteroarene or R^(49A); R^(49A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; wherein themoieties represented by R⁴², R^(42A), R⁴³, R^(43A), R⁴⁴, R^(44A), R⁴⁷,R^(47A), R⁴⁸, R^(48A), R⁴⁹, and R^(49A) are independently substitutedwith one or two or three or four of independently selected R⁵⁰, OR⁵⁰,SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰, CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂,NHR⁵⁰, N(R⁵⁰)₂, NHC(O)R⁵⁰, NR⁵⁰C(O)R⁵⁰, NHS(O)₂R⁵⁰, NR⁵⁰S(O)₂R⁵⁰,NHC(O)OR⁵⁰, NR⁵⁰C(O)OR⁵⁰, NHC(O)NH₂, NHC(O)NHR⁵⁰, NHC(O)N(R⁵⁰)₂,NR⁵⁰C(O)NHR⁵⁰, NR⁵⁰C(O)N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂,C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁰SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰,SO₂N(R⁵⁰)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI; R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴; R⁵¹is phenyl, which is unfused or fusedwith benzene, heteroarene or R^(51A); R^(51A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁵² is heteroaryl,which is unfused or fused with benzene, heteroarene or R^(52A); R^(52A)is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R⁵³is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(53A);R^(53A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁵⁴ is alkyl, alkenyl or alkynyl, each of which isunsubstituted or substituted with one or two or three of independentlyselected R⁵⁵, OR⁵⁵, SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, C(O)R⁵⁵, CO(O)R⁵⁵, OC(O)R⁵⁵,OC(O)OR⁵⁵, NH₂, NHR⁵⁵, N(R⁵⁵)₂, NHC(O)R⁵⁵, NR⁵⁵C(O)R⁵⁵, NHS(O)₂R⁵⁵,NR⁵⁵S(O)₂R⁵⁵, NHC(O)OR⁵⁵, NR⁵⁵C(O)OR⁵⁵, NHC(O)NH₂, NHC(O)NHR⁵⁵,NHC(O)N(R⁵⁵)₂, NR⁵⁵C(O)NHR⁵⁵, NR⁵⁵C(O)N(R⁵⁵)₂, C(O)NH₂, C(O)NHR⁵⁵,C(O)N(R⁵⁵)₂, C(O)NHOH, C(O)NHOR⁵⁵, C(O)NHSO₂R⁵⁵, C(O)NR⁵⁵SO₂R⁵⁵, SO₂NH₂,SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁵, C(N)N(R⁵⁵)₂,CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl,Br or I; R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and wherein eachforegoing cyclic moiety is independently unsubstituted, furtherunsubstituted, substituted or further substituted with one or two orthree or four or five of independently selected R^(57A), R⁵⁷, OR⁵⁷,SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, OC(O)R⁵⁷, OC(O)OR⁵⁷, NH₂,NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷, NR⁵⁷C(O)R⁵⁷, NHS(O)₂R⁵⁷, NR⁵⁷S(O)₂R⁵⁷,NHC(O)OR⁵⁷, NR⁵⁷C(O)OR⁵⁷, NHC(O)NH₂, NHC(O)NHR⁵⁷, NHC(O)N(R⁵⁷)₂NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷)₂, C(O)NH₂, C(O)NHR⁵⁷, C(O)N(R⁵⁷)₂,C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷, C(O)NR⁵⁷SO₂R⁵⁷, SO₂NH₂, SO₂NHR⁵⁷,SO₂N(R⁵⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁷, C(N)N(R⁵⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI; R^(57A) is spirocyclyl; R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹ ; R⁵⁸ is phenyl,which is unfused or fused with benzene, heteroarene or R^(58A); R^(58A)is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R⁵⁹is heteroaryl, which is unfused or fused with benzene, heteroarene orR^(59A); R^(59A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(60A); R^(60A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁶¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three of independently selected R⁶², OR⁶², SR⁶², S(O)R⁶², SO₂R⁶²,C(O)R⁶², CO(O)R⁶², OC(O)R⁶², OC(O)O⁶², NH₂, NHR⁶², N(R⁶²)₂, NHC(O)R⁶²,N⁶²C(O)R⁶², NHS(O)₂R⁶², N⁶²S(O)₂R⁶², NHC(O)OR⁶², N⁶²C(O)OR⁶², NHC(O)NH₂,NHC(O)NH⁶², NHC(O)N(R⁶²)₂, N⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂,C(O)NHR⁶², C(O)N(R⁶²)₂, C(O)NH0H, C(O)NHOR⁶², CfOJNHSO₂R⁶²,C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NHR⁶², SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁶², C(N)N(R⁶²)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I; R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶; R⁶³ isphenyl, which is unfused or fused with benzene, heteroarene or R^(63A);R^(63A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁶⁴ is heteroaryl, which is unfused or fused withbenzene, heteroarene or R^(64A); R^(64A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁶⁵ is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, each of which is unfused orfused with benzene, heteroarene or R^(65A); R^(65A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁶⁶ is alkyl,alkenyl or alkenyl, each of which is unsubstituted or substituted withone or two or three of independently selected R⁶⁷, OR⁶⁷, SR⁶⁷, S(O)R⁶⁷,SO₂R⁶⁷, C(O)R⁶⁷, CO(O)R⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷, NH₂, NHR⁶⁷, N(R⁶⁷)₂,NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷, NHC(O)OR⁶⁷,NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂, NR⁶⁷C(O)NHR⁶⁷,NR⁶⁷C(O)N(R6 ⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂, C(O)NHOH,C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NHR⁶⁷, SO₂N(R⁶⁷)₂,C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH, CNOCH3, OH, (O),CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; wherein themoieties represented by R^(57A), R⁵⁸, R⁵⁹, R⁶⁰, R⁶³, R⁶⁴, R⁶⁵, and R⁶⁷are unsubstituted or substituted with one or two or three or four ofindependently selected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸, SO₂R⁶⁸, C(O)R⁶⁸,CO(O)R⁶⁸,OC(O)R⁶⁸, OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂, NHC(O)R⁶⁸,NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸, NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸, NR⁶⁸C(O)OR⁶⁸,NHC(O)NH₂, NHC(O)NHR⁶⁸, NHCC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸, NR⁶⁸C(O)N(R⁶⁸)₂,C(O)NH₂, C(O)NHR⁶⁸, C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸, C(O)NHSO₂R⁶⁸,C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂, SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I; R⁶⁸ is R6 ⁶⁹, R⁷⁰, R⁷¹ or R⁷²; R⁶⁹ isphenyl, which is unfused or fused with benzene, heteroarene or R^(69A);R^(69A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁷⁰ is heteroaryl, which is unfused or fused withbenzene, heteroarene or R^(70A) ; R^(70A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁷¹ is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, each of which is unfused orfused with benzene, heteroarene or R^(71A); R^(71A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁷² is alkyl,alkenyl or alkenyl, each of which is unsubstituted or substituted withone or two or three of independently selected R⁷³, OR⁷³, SR⁷³, S(O)R⁷³,SO₂R⁷³, C(O)R⁷³, CO(O)R⁷³, OC(O)R⁷³, OC(O)OR⁷³, NH₂, NHR⁷³, N(R⁷³)₂,NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³, NHC(O)OR⁷³,NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂, NR⁷³C(O)NHR⁷³,NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂, C(O)NHOH, C(O)NHOR⁷³,C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³, SO₂N(R⁷³)₂, C(O)H,C(O)0H, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I; R⁷³ is alkyl, alkenyl,alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkylor heterocycloalkenyl; and the moieties represented by R⁶⁹, R⁷⁰ , andR⁷¹ are unsubstituted or substituted with one or two or three or four ofindependently selected NH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃,C(O)H, C(O)OH, C(N)NH₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃,OCF₂CF₃, F, Cl, Br or I. 2-12. (canceled)